Sciencemadness Discussion Board

pyridine prep help

LoKi - 27-2-2007 at 03:59

I was wondering if anyone had any ideas for a Pyridine prep. I remember reading a text saying that the general procedure for producing pyridines was the Haantz reaction? I don't remember the name off the top of my head, but I know that it gave shit other than simple pyridine. there was a variation that gave some sort of 3,5 substituted pyridine. Thats great and all but what about simple old pyridine? Would it be possible to cleave the ethers or alkyl chains or whatever it was sticking off? The pyridine ring is pretty strong if I remember correctly, so I guess you could subject it to all kinds of torture. I know, I oughta look up the reaction and be specific instead of pulling this info out my ass, but I'm tired and about to go to bed, and I think I got my point across. Apologies for typos and nonsensical ramblings. Like I said, I'm REAL tired. Anyway, any help would be greatly appreciated.

Sauron - 27-2-2007 at 10:39

I will look into this for you. Never really considered it before, pyridine being an easy chemical to buy.

Niacin (nicotinamide) is also easy to buy and you can decarboxylate it, it is pyridine-3-carboxamide.

Magpie - 27-2-2007 at 19:08

Conversion of niacin (nicotinamide) to pyridine sounds like an interesting synthesis for the home chemist. This presumes that one can isolate the nicotinamide in sufficient purity from the OTC niacin concoctions. It should then be readily convertible to nicotinic acid utilizing HCl.

Could the nicotinic acid then be decarboxylated to pyridine in the same way benzoic acid is decarboxylated to benzene?

leu - 27-2-2007 at 19:14

This has been discussed in detail on a site long gone from the internet. Psyloxy did most of the legwork :) It's not practical, see:

1.5 g nicotinic acid and 2.5 g CaCO3, when heated to decarboxylation with a bunsen burner give 0.3 mL pyridine not worth the hassle, nicotinic acid is also quite expensive.

There's Patent DE944251:

Example 2

A solution of 200 parts 1,5-pentanedial in 800 parts 3% sulfuric acid is added, over the course of 2 h, to a boiling solution of 1100 parts crystallized Fe2(SO4)3 and 200 parts (NH4)2SO4 in 1500 parts water. Workup as in example 1 yields 82% pure pyridine.

workup as in example 1: rxn-mixture is made alkaline and the aromatic base is distilled off.

The dehydrogenation of piperidine forming pyridine can be carried out either by heating to 300° with concentrated sulphuric acid, or with nitrobenzene at 200°; or with silver acetate in acetic acid.

[Edited on 28-2-2007 by leu]

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Sauron - 27-2-2007 at 19:24

A lot more people are interested in making piperidine than in making pyridine.

This includes making piperidine from pyridine (which is rather easy).

guy - 27-2-2007 at 22:43

Aldol condensation of formaldehyde with acetone(should have vrey good yield since formaldehyde is a good electrophile). Then add ammonia(conjugate addition + intramolecular cylclization) = piperdone. Reduce the carbonyl = piperidine. Looks good on paper.

[Edited on 2/28/2007 by guy]

Sauron - 27-2-2007 at 23:42


Generally you cyclize something like 5-aminopentyl bromide or similar 5-carbon backbone, it's not that tough.

However if you have a ready supply of pyridine, then reducing it with sodium in ethanol is easier. This also assumes you have a lot of sodium or can get it.

I use dilute piperidine soln for global deprotection of Fmoc peptides as it works a lot better than NMM (N-Methylmorpholine.)

leu - 28-2-2007 at 02:54

An old preparation of piperidine is by heating pentamethylenediamine hydrochloride (cadaverine); which is the result of putrefactive enzymes on lysine; ii's quite toxic in addition to being very obnoxious, but the hydrochloride salt isn't so toxic :P An alternative synthesis can be found in Ber 56 625-30 (1926):

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Sauron - 28-2-2007 at 04:50

Thanks, @leu

Cadaverine is very expensive. It is classed as corrosive, nothing special is said about toxicity. Acros wants $10 a gram for it and does not have more than 25 g bottles.

On the other hand, the corresponding glycol is cheap and sold by the Kg ($66) so building the diamine from that via the dihalide would be easy.

Another related route might employ tetrahydropyran, but it is about 50% more expensive than the glycol, and being an ether will be prone to peroxide formation. The transformation to the open chain glycol would be similar to taking THF to BDO.

Incidentally these N and O saturated heterocycles sometimes do odd things.

When one of the Big Pharmas was developing Ditran as an experimental psychiatric drug they had this problem.

Ditran was a an ester of a tetrahydrofurfuryl carboxylic acid. They started with tetrahydrofurfuryl alcohol, an agricultural byproduct from Quaker Oats mostly. Made the bromide then the amine. But when this was distilled they didn't obtain the single pure tetrahydrofurfurylamine, they got a mixture of it with 3-hydroxypiperidine. The furan ring had opened, and the open chain intermediate reclosed as the six membered imine.

This observation led to the development of the 3-quinuclidinyl benzilates (BZ etc).

That piperidine ring is really very favored, chemically.

[Edited on 28-2-2007 by Sauron]

not_important - 28-2-2007 at 08:14

Hmmm ... adipic acid, if you don't have a direct source then the hydrolysis of nylon-6-6 will yield it and the matching C6-diamine, convert to the diammonium salt, heat to form the cyclic amide, treat with NaOCl giving 5-amino-pentanoic acid. That should cyclicize to the amide, 6 member rings being favoured. Reduce the amide to piperidine.

Hexamethylene diamine is similar to cadaverine, maybe a bit less stinky. If you xan put together a setup to avoid the escape of the diamine and don't live well away from other people, acid hydrolysis is advisable to keep the diamine as the salt.

Sauron - 28-2-2007 at 09:10

I think I'll stick to Na/EtOH redn of Pyridine...

Cadaverine does sound like the Smell-O-Rama version of Jeepers Creepers. Ugh.

LoKi - 28-2-2007 at 10:39

I didn't realize pyridine was easy to come by. I seem to remember hearing it was watched, but not listed. The niacin decarboxylation looks interesting, I'll give it a shot and see how it goes. Fairly pure niacin should be available from several vitamin retailers. Guy- that aldol condensation sounds a lot like that Hantzsch Pyridine Synthesis that I had mentioned. Thanks so much for help, fellas.

Sauron - 28-2-2007 at 11:56

"watched but not listed" is just druggie paranoia. Look at all the totally irrational stuff on their lists, and ask yourself whether or not they would deliberately leave off anything they thought was significant?

These are the folks who banned Red Devil lye remember.

pantone159 - 28-2-2007 at 12:42

Originally posted by Sauron
These are the folks who banned Red Devil lye remember.

Which is not listed, and so a specific example of something left off the list that is thought to be significant.

Sauron - 28-2-2007 at 18:24

Well, then I was wrong because they haven't banned Red Devil lye, but, you can also bet your ass that there's no DEA agent lurking in every supermarket, 7-11 and hardware store checking on who buys drain cleaner.

It's ridiculous. It's a waste of manpower, and unproductive.

Magpie - 28-2-2007 at 18:54

Not drain cleaner but my local hardware store requires that the buyer provide his name, signature, and driver's license number when buying acetone, toluene, and another solvent that I can't remember. This is kept on a log sheet. I don't think this was inspired by the DEA but likely by the local constabulary. Ridiculousness is not a factor.

Sauron - 1-3-2007 at 01:43

Maybe I am old fashioned, but, if a clerk in a hardware store was arrogant enough to ask me (a paying customer, and not at all up to no good) for all that just to buy a tin of a common solvent (toluene = paint remover, acetone = degreaser) I would walk out and find another store. If the county Mounties mandated that I'd drive to a county where they still respected the privacy of honest citizens.

It IS ridiculous.

If the stuff is so hazardous to the public safety by virtue of the assholery of meth cooks, jihadis, whatever, take it off the store shelves. But if it is available to the public, OTC, then by God it is nobody's business who buys it and the gubbiment ought not to be turning counter clerks into spies and snoops.

evil_lurker - 1-3-2007 at 03:25

I'd be like suuuuuurrrrrreeeeee... put my name on the log.

After you raided 99.9% of the persons on the list, you MIGHT get one meth cook... wait though.. I'm thinking that was BEFORE the pseudoephedrine restrictions...

Those logs are useless nowadays. Pure scare tactic is all it is.

Magpie - 1-3-2007 at 09:25

My comment on "ridiculousness" was poorly worded. Of course it is ridiculous. What I was trying to say is that LE and the store management don't let that fact stop them.

The clerks are not arrogant. They are merely minimum wage pawns in this farce that need to keep their jobs.

I don't buy solvents at that hardware store anymore. I drive 5 miles down the road and give my business to their competitor who fortunately doesn't care to play these silly games.

And yes, Lurker, this has all been made moot by the bans on OTC pseudoephedrine anyway. It simply is just intimidation of the innocent.

[Edited on 1-3-2007 by Magpie]

Sauron - 1-3-2007 at 11:10

Of course we are all preaching to the choir.

And you are doing just what I said I'd do, go buy somewhere less nosy.

Sure the clerk is just doing what he's told. Unless the clerk is the owner, and then he's doing what he chooses, I don't think local LE can force him to do this, so it's his choice and that would make him arrogant.

Does 5 miles away get you across a county line, or out of city limits? How local is local?

Magpie - 1-3-2007 at 11:29

Rather than call the store management (or owner) "arrogant," I would call them politically correct wimps.

No, 5 miles is still in the city. But the owner is local, old, and crusty, and has apparently chosen not cave in to this bullshit busywork that LE wanted to foist on him.

Sauron - 1-3-2007 at 12:16

Okay maybe arrogant is not quite right, but, presumptuous. If I go buy a wrench the seller doesn't ark me what I want it for. All the same, tool, or supply like degreaser or paint remover. Those stores are there to sell such things and not to collect names for the Nanny State.

I have nothing at all to hide but I would go a lot farther than five miles to get away from that sort of intrusion into my privacy and I would not give that place of business one dollar of my trade, ever again, for any reason.

Good on your crusty old shopkeeper, I bet we'd see eye to eye.

LoKi - 1-3-2007 at 23:50

I really have nothing to hide either, but having the city's finest rummaging through my makeshift and very fragile lab is the last thing I want, which is why I would rather make my own reagents if they can't be bought at the hardware store or online. Maybe once my balls will drop and I'll try to purchase my supplies at the local chem distributor. I certainly don't want to fill out an "intended use" form or whatever they call it. Most of the things I buy, I buy only with a vague idea about what I'll use it for. I just want to try different reactions and learn the trade and gain experience. Speaking of filling out forms at stores, a law was recently passed in my state requiring strict records of psuedoephedrine, ephedrine, and PPA to be kept by all retailers. ID's are to be shown, addresses recorded, signatures, the whole nine yards. There is also a buying limit of something like 2 boxes a month. Working at a pharmacy, I hear stories about the DEA bitching like, well, a bitch, when the kids at the register don't follow their regulations to the letter. It's disgusting, and meth isn't even a problem here. I looked up the statistics, there has been ONE meth found in this county, ever. Statewide meth use and manufactor statistics are relatively low as well.

Sauron - 2-3-2007 at 03:50

However, I assume you do not feel deprived by not being able to buy ephedrine, psuedoephedrine, or PPA? I know I don't.

1. I would not stop me from doing chemistry in the slightest.

2. It would not stop me from making methamphetamine if I was so inclined, either, because there are beaucoup ways to do that which have nothing to do with ephedrine, psuedoephedrine, or PPA.

So you see, that measure ONLY affects meth cooks who were using those immediate precursors in that particular route or two.

pantone159 - 2-3-2007 at 07:38

Originally posted by Sauron
So you see, that measure ONLY affects meth cooks who were using those immediate precursors in that particular route or two.

Or those who actually want a decongestant. From what I hear, the replacement chemical doesn't work.

Sauron - 2-3-2007 at 07:49

My recollection was that FDA had unrelated reasons for replacing those compounds in OTC decongestants.

You seem to be arguing that DEA did it to inconvenience cold sufferers.

I think that is erroneous; this is what we call collateral damage.

DEA didn't do it, FDA did, because they and not DEA are the cognizent authority. And their reasons had nothing to do with law enforcement issues. I specifically remember a big flap about health issues surrounding PPA.

pantone159 - 2-3-2007 at 08:26

I remember (do not have references now, however) peer-reviewed studies of the pseudoephedrine replacement that conluded that it did not work, as well as multiple less-rigorous reports indicating same.

I've never heard of health concerns about pseudoephedrine, unlike e.g. acetaminophen which is actually quite dangerous in many cases.

I think the reasons for eliminating pseudoephedrine are nearly entirely about meth production. As always, when public health and the Drug War conflict, the Drug War wins.

Sauron - 2-3-2007 at 08:45

There was a public health issue about PPA, not only in US but in EU and worldwide, even in Thailand.

Those reports indicated PPA was dangerous.

Your reports merely question whether or not the replacement was effective.

Replacing a dangerous decongestant with an inneftive one, is not good public health policy?

Admittedly, replacing it with an effective sunstitute would be better.

I don't have any references either, which makes us even.

I really don't think the absence of an OTC cold remedy ingredient, or three, constitutes a threat to the public health.

Whereas methamphetamine most assuredly does.

Now don't misunderstand me. I don't think banning sudafed etc is an effective countermeasure. It is just as asinine as the meth cooks who were buying cold pills in bulk to get pseudoephedrine a few mg at a pop. Stupid.

LoKi - 2-3-2007 at 22:32

Sauron, no I don't feel deprived of p-fed to make meth. I have no desire to make it, use it, or be around people who use it. I am not mistaken about the DEA however. This regulation falls under the "Combat Mehtamphetamine Act of 2006." It is not the FDA, but the DEA who pushed for the bill and are responsible for its regulation. Personaly I don't even use cold medications, but my mom loves Drixoral, and buys several packages of the strongest stuff at a time, and I know she is not to happy. Of course they didn't do this merely to inconvienence law-abbiding citizens, but that is likely the only thing that will happen. Meth is practicly non-existant here, what is around comes from Mexico (I am going off of what the DEA says on their website), and as you said, if one wanted to make meth, they would make it regardless of any regulations. BTW, this might only apply to Ohio.

[Edited on 3/3/07 by LoKi]

pantone159 - 3-3-2007 at 07:54

Originally posted by Sauron
"watched but not listed" is just druggie paranoia.

This is false.

See this link, from the DEA website, that has a "Special Surveillance List Published Pursuant to Title 21, United States Code, Section 842(a)(11)", specifying the following chemicals, including pyridine... (a couple of these have moved up to the official List I)

* Ammonia Gas
* Ammonium Formate
* Bromobenzene
* 1,1-Carbonyldiimidazole
* Cyclohexanone
* 1,1-Dichloro-1-fluoroethane (e.g. Freon 141B)
* Diethylamine and its salts
* 2,5-Dimethoxyphenethylamine and its salts
* Formamide
* Formic Acid
* Hypophosphorous Acid
* Lithium Metal
* Lithium Aluminum Hydride
* Magnesium Metal (Turnings)
* Mercuric Chloride
* N-Methylformamide
* Organomagnesium Halides (Grignard Reagents) (e.g. ethylmagnesium bromide and phenylmagnesium bromide)
* Phenylethanolamine and its salts
* Phosphorus Pentachloride
* Potassium Dichromate
* Pyridine and its salts
* Red Phosphorus
* Sodium Dichromate
* Sodium Metal
* Thionyl Chloride
* ortho-Toluidine
* Trichloromonofluoromethane (e.g. Freon-11, Carrene-2)
* Trichlorotrifluoroethane (e.g. Freon 113)

Sauron - 3-3-2007 at 08:34

A lot of those are scheduled chemicals on the Chemical Warfare Convention, and DEA says they watch them because of that.

Another waste of time, of course.

S.C. Wack - 3-3-2007 at 15:25

Originally posted by Sauron
A lot of those are scheduled chemicals on the Chemical Warfare Convention, and DEA says they watch them because of that.

Oh? Where exactly do they say that they watch them because of the "Chemical Warfare Convention"?

That is an odd interpretation of "Special Surveillance List of Chemicals, Products, Materials and Equipment Used in the Clandestine Production of Controlled Substances or Listed Chemicals". Each and every chemical on that list, and in lists 1 and 2, is on the list because of potential for utilization in drug manufacture. Really.

Yes, it was inevitable that as soon as the discussion turns to the DEA and legal issues, I magically appear.

Sauron - 3-3-2007 at 18:57

Thionyl chloride AFAIK is not a specific drug precursor. It's a specific CW precursor, for one route to "mustard gas" and that's why it is on CWC - because Saddam bought so very much of it.

It's a general reagent for acyl chlorides. And alkyl chlorides.

Phosphorus pentachloride isn't a specific drug precursor. It is however a specific CW precursor (OPs) and that's why it is on CWC.

It's a general chlorinating agent and dehydrating agent.

Dimethylamine is a specific precursor for GA. That's why it's on CWC. I can only think of a single drug preparation where it is used and that is DMT. How much of a DMT cottage industry is there? I would guess, not much. Not compared to many other more popular abuse drugs.

Don't misunderstand me, I think this is silly shit, both CWC and this list and all the lists. All Grignard reagents, Mg turnings, as if amyone doing a Grignard must be making drugs. Now which one of these is true?

Anyone performing a Grignard MUST be making drugs

Anyoen performing a Grignard PROBABLY is making drugs

Anyone performing a Grignard MIGHT be making drugs.

Anyone performing a Grignard COULD be making drugs.

The only fairly meaningful statement is the last one, and it is insufficient in the absence of collateral information, to make an assesment. Because the simple fact is that someone performing a Grignard COULD be making damn near anything. Because the Grignard rxn isn't about drugs, it's about making C-C bonds.

S.C. Wack - 3-3-2007 at 19:15

SOCl2 is highly useful in making drug precursors and reagents. Also the P chlorides. The chemicals placed on the DEA lists did not get there by accident.

Sauron - 3-3-2007 at 19:51

Enumerate the specific drug preps in which thionyl chloride plays a part. I'm all ears.

Not meth, not PCP, not the substitutes amphetamines, that I know of. I do not claim (nor do I aspire to) an exhaustive knowledge of the subject, but, I draw a blank.

On the other hand, I do know what it's all about in CW. And of course the really silly thing there is that the "German methos" for making mustard is far from the best methos. And even within the German method, there are many other chlorinating agents, other than SOCl2, that can and have been used, including conc Aq HCl. I can think of at least 3-4 alternatives for chlorinating thiodiglycol. SOCl2 has simply been demonized because it's how the SAddam regime elected to do it. Also their counterparts in Iran. Money clearly was no object to them and neither did they strive for self sufficiency or they would have gone in for ethylene + SCl2.

How about HgCl2? That's a mystery to me. Used to activate Al for pinacol prep from acetone, which makes it vaguely in the CW thing on the way to pinacolyl alcohol but, drug preps?

Some things on that list are quite specific. o-toluidine, OK, methaqualone. They have the other requisite, anthranilic acid covered elsewhere, half-assedly.

Cyclohexanone is a no brainer, along with bromobenzene, PCP.

And formamide, formic acid, N-Meformamide, all speak to the Leuckart.

Not that these are hard to make anyway.

But some of the others are less transparent, and seem to me to be mostly, or solely, CW concerns (and lame ones at that.)

S.C. Wack - 3-3-2007 at 20:52

thionyl chloride
mercuric chloride

As for the original question, pyridine synthesis has come up here before. Hard to believe.

[Edited on 4-3-2007 by S.C. Wack]

Sauron - 3-3-2007 at 21:23

Okay, point taken.

However, they are still general reagents for thousands, or tens of thousands of perfectly legitimate synthetic and technical applications.

Are they not? Of course they are.It is long evident that the war on drugs is a rout. Every year the supply increases and the price goes down. This is a dismal failure.

Within the larger picture of this dismal rout, the attempt to cut off access to precursors, reagents and solvents is a counterproductive waste of time and manpower. It amounts to busywork for the LE people. It might inconvenience the wannabe drug cooks, but not the more significant ones who always know how to evade such efforts, are resourceful and have the means to obtain what they need.

In my part of the world, acetic anhydride is banned and has been for a long time, however this has obvious done nothing to stop heroin from being manufactured - just shifted it across the border to Burma and Laos where it is essentially a government enterprise. Meanwhile diplomats wheedle with the Burmese and the Lao trying to entice them to kill the fatted calf. Little chance of that happening. So what good is the ban on Ac2O? None that I can see.

visitation123 - 29-4-2007 at 14:46

The pseudoephedrine replacement phenylephrine doesn't work, try it. It wont unblock a single nose or get you high (albeit just a little) :D

Pseudoephedrine had off-label uses too, it was good for chronic bronchitis and hayfever in my experience, now I have to rely on steam. It's been banned in Australia too.

'Pseudoephedrine may relax bronchial smooth muscle by stimulation of b -adrenergic receptors

phenylephrine causes a reduction or no change in cardiac output, that's what psuedoephedrine was good for getting you high, you can't get high of phenylephrine, it's useless for all purposes it's like taking a placedo.

P.S. You can buy pyridine from a chemical supplier, acetone' suspicious too, but they don't have the resources to nag everyone who buys any of these chemicals except the most suspicious chemicals, and pyridine ain't one of those mate. Besides, your an innocent, curious individual like me, so if they do come, who cares?

[Edited on 29-4-2007 by visitation123]