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Microwave-Assited Rapid and Simplified Hydrogenation

Thu Feb 10, 2005 10:22 pm

  Microwave-Assited Rapid and Simplified Hydrogenation

Author  Topic:   Microwave-Assited Rapid and Simplified Hydrogenation 
PimpBee   posted 10-18-1999 06:16 PM          
Okay, my fellow bees. Threads here at the Hive have been getting rather lame in that no real breakthroughs have been posted (just a rehash of old methods). Well, with the start of this thread, I'm going to change all that.
This bit of news is probably -- I dare say -- THE find of the year. Yes, you read the title correctly: MICROWAVE-ASSISTED RAPID AND SIMPLIFIED HYDROGENATION. And boy, is it ever rapid and simplified. What promise it does hold!

The two experimental details that caught my eye (aside from the unbelievably high yielding and facile process) were the hydrogenolysis of an acetyl ester and phenylhydrazone.

But first, I offer you the process as it is laid out:

"General Proceedure for CTH Reaction:

On the basis of several years of experience, we have found the following protocol to be safe for conducting catalytic transfer hydrogenation. Caution must be exercised, however, since some of the catalysts are pyrophoric; also, mixtures of hydrogen and air can cause and explosion if if ignited by a spark or a flame. An UNMODIFIED DOMESTIC MICROWAVE OVEN (my caps) (600-1000 W) placed a hood should be used. The reaction vessel should be a beaker or an Erlenmeyer flask of fairly large size. A beaker of water should be placed near this reaction vessel to serve as a 'heat sink' to provide a finer control on the amount of microwave energy input into the hydrogentation mixture. Water absorbs microwave energy very efficiently and thereby reduces the amount of energy absorbed by the reaction mixture. The approximate amount of water to be used can be determined with a trial run involving only the solvent and without the catalyst.

"The desired temperature of the solvent should rise to 110-120 deg C in about 3 minutes. The catalyst should be quickly introduced into the reaction vessel and covered with the solvent (such as ethylene glycol, bp 198 deg C) and made into a slurry by gentle swirling motion of the beaker or the conical flask. The compound to be reduced is dissolved in the solvent (ethylene glycol or 1,3-propandiol) and then added the reaction vessel. The hydrogen donor (such as ammonium formate) is added now. Microwave irradiation for the pre-determined time to reach a temperature of 110-130 deg C should be applied. The microwave oven door should be opened, and the temperature of the reaction mixture should be checked to be in the desired temperature range.

"The oven door should be closed and irradiation with microwave should be resumed for another 3-4 min. The microwave oven should be switched off, and the reaction vessel removed from the oven. Careful decantation of the reaction mixture after cooling followed by the addition of glycol to the reaction vessel would preserve the catalyst for the next experiment.

"It is customary in our laboratory to place a beaker cover or a filter funnel on top of the reaction vessel to prevent any accidental spillage. Since glass is nearly transparent to microwaves, the upper parts of the beaker or flask serves as a condenser for any small amounts of vapors formed. After the hydrogenation the reaction mixture was cooled and then filtered. The filtrate was diluted with water and extracted with ethyl acetate, and the organic layer was washed with water. Evaporation of the solvent from the organic layer (dried over anhydrous Na2SO4) followed by crystallization gave the pure product in 80-90% yield. We have observed that the optimal ratio of the catalyst (10% Pd/C) to substrate is 0.3:1 by weight for each reducible group. Five equivalents of ammonium formate for each reducible group gave good results."

So what's so significant about all this? Well, mainly that one can now perform catalytic hydrogenations -- normally done under pressure (30-40 Ibs) with flammable hydrogen gas which normally takes anywhere form 4 to 24 hours to complete -- with a hydrogen donor (ammonium formate) in an unmodified microwave oven, safely and efficiently in under 10 minutes! According to the authors, no typical laboratory equipment is needed to perform the hydrogenation. Since microwave energy contacts each polar molecule at once, there is no need for magnetic stirring. Since a high boiling solvent is used, elevated temperatures can be reached without the need for a reflux apparatus, and so on and so on . . .


(Am I the only one who is impressed here?)

So what are the applications?

Well, in the paper -- which is practically hot off the press (JOC, 1999, 64, 5746-5753) -- experimental model number 26 has an acetyl ester which when run through the microwave catalytic hydrogenation process, is reduced and deacetylated to a methylene group.

Does this ring a bell?

Well, those of you familiar with Fester's new process (you know, the one in his video) know that the intermediate he uses to get to his final product is the acetyl ester of "feed stock". So if one were to deviate from the normal proceedure Fester has laid out for us by evaporating the acetic acid solution to isolate the acetic acid ester and them move on to using it in the CTH (Catalytic Transfer Hydrogenation) reaction, one could possibly have, oh, about say 10 minutes later, a good sample of a very popular and desirable stimulant in approximately 80-90% yield!

And what if one used 2,5-dimethoxy-nitrostyrene? Would one end up with the desired amine? I say at least possibly and quite probably. But to find out, any bee interested would only have to experiment cheaply and safely and in what is obviously a very short period of time.

As for the other part of the paper that caught my eye, well, here's another direct quote:

"Hydrazones are formed in excellent yield in minutes under microwave irradiation of ketones . . . with hydrazine or phenylhydrazine in ethylene glycol solution. . ."

Phenylhydrazine is the actual compound that they use in their experimental model. If I remember its profile correctly, it is neither very toxic substance nor very expensive.

Continuing on:

"Such hydrazones can be converted to amines by microwave-assisted CTH reaction . . . in 90% yield in 6 minutes . . ."

So if one were to use our ever-lovely ketone in this reaction, (possibly even undistilled dirty ketone) one could isolate the hydrazone formed and then reduce it using the aforementioned CTH reaction.

For those interested, here is the actual process:

"Methyl benzoyl formate (ketone; 6.1 mmol), phenyl hydrazine (7 mmol) and ethylene glycol (5 mL) were placed in an Erlenmeyer flask (125 mL). The mixture was heated for 6 min. at low power setting. The desired phenyl hydrazone precipitated out on scratching under ice-cold condition. It was filtered, washed with hexane, and dried (yield 90%, mp 86-88 deg C).

"Ammonium formate (200 mg) and 10% Pd/C (100 mg)were added to phenyl hydrazone (2 mmol) in ethylene glycol (5 mL). The mixture was irradiated for 4 min. After the usual work-up, the amine was isolated (92%).

Any comments?

I better get some feedback on this one . . .


Hive Bee   posted 10-18-1999 07:39 PM          
Psychokitty I for one am fully impressed! This has to bee the simpliest quickest procedure I have seen yet, using the simpliest equipment imaginable. It is surely in reach of even the most pathetic of wannabe chemists, let alone the talent of the hive.
I expect this topic is going to bee popular...

Pimp Master   posted 10-18-1999 08:01 PM          
Fucking awesome. nice find.

Hive Bee   posted 10-18-1999 08:22 PM          
Sounds interesting. But could this type of reaction lead to polymerization of the ketone? What about reduction of the dioxy bridge? Are there desriptions of reductive alkylations alread available? If these ?'s have already been answered in previous microwave discussions I apologize.

Hive Bee   posted 10-18-1999 10:58 PM          
This is quite a find pyschokitty,...
But again the demon of Pd/C arises,...

Hopefully, for this experiment you are useing l-ephedrine or d-pseudoephedrine, because the Pd/C causes inversion of the molecule. I'm pretty sure that OTC ephedrine is l-ephedrine and d-pseudoephedrine, but I'm not positive becuase I haven't seen any concrete reference on it.
"Organic Reactions", Editor in Cheif ROger Adams, 1953, page 290 lists, in a table, the reduction of ephedrine-HCl in acetic acid and HClO4 @ 80-90 C, @ 1 atmosphere on Pd/BaSO4 to methedrine-HCl in 10 minutes, so this mircowave route probably does even better! (If at all possible)

So big questions need to be answered first before this inducted into the hall of fame.

1) Is ammonia Formate the only hydrogen source possible, and what are other possiblities?
2) The optical rotation of OTC ephedrine. Which then dictates if Pd is a good hydrogenation catalyst (because of Pd inverting the molecules rotation)

This thread rules.

Pimp Master   posted 10-19-1999 02:40 PM          
Kitty: Good find! Just one note - you're right in that phenylhydrazine isn't expensive, but it is VERY poisonous...
Chemguy: What's wrong with ammonium formate?

Hive Bee   posted 10-19-1999 04:49 PM          
I think that no preparation of a hydrogen source would be easier. For ammonium formate, you need to first get NH3 then HCOOH and we all know how many bee's have difficultly in aquiring the simplest of chemicals, let alone a procedure which involves,.... adiition! (Gasp!)
All I want is an option or two, that's all. A wide base of knowledge never hurt anyone's chance at sucess...

PimpBee   posted 10-19-1999 06:07 PM          
The paper lists several other hydrogen donors that have been used which include cyclohexane, hydrazine, formic acid, cyclohexadiene, and phosphinic acid. But according to them, ammonium formate was by far the most safe and convenient to use.
One essential aspect to the reaction that I forgot to mention is that the flask or beaker used must provide a shallow liquid base. So probably, if one were to get into the 100 mmol substrate range, a 2000 mL beaker or so would be called for. But that's not really a problem. At least to me it isn't.

As for the pyrophoric nature of the catalyst, I was thinking that maybe a different palladium catalyst could be used -- something like that of the Royer, which does not have a flammability liability.


Hive Bee   posted 10-19-1999 06:19 PM          

I'm pretty sure that OTC ephedrine is l-ephedrine and d-pseudoephedrine, but I'm not positive becuase I haven't seen any concrete reference on it.

Harry F. Skinner Forensic Science International, 48 128-134 (1990)[

methedrine Synthesis Via HI/Red Phosphorous Reduction of Ephedrine

The most common method of manufacture of methedrine in the United States is the reduction of ephedrine with hydriodic acid and red phosphorus (HI/red P) [1]. Manufacture of methedrine from phenyl-2-propanone (P2P) and methylamine yields (+,-)methedrine, whereas the reduction of
(-)ephedrine or (+)pseudoephedrine yields (+)methedrine.

Well, that seems pretty concrete to me. The whole article is here, in case you're interested:



Hive Bee   posted 10-19-1999 06:23 PM          
Grrr...I have a hard time getting the UBB code right, dammit! http://rhodium.lycaeum.org/chemistry/-----hi-redp.txt 
Psychokitty: Most interesting. Thanks for digging it up. I shall definitely bee following this discussion, even if I don't know enough to contribute!


Hive Bee   posted 10-19-1999 06:50 PM          
I know the article you speak of, and I even have a photocopy of it, but the article is dated 1990, well before all of the ephedrine controll acts had been past. Back when that article was written you could buy bottle of pure ephedrine over the counter at any GNC or supermarket. Alas, times have changed, and I'm pretty sure that when the DEA decided to make ephedrine conversion more difficult.
Also, that article states that the HI/RedPhosphorus route reduces common ephedrine to d-methedrine. The HI/RedPhosphuros method causes no inversion of the rotation of the amine, which means that if this article was still correct, then Pd/C would produce an inverted amine chirality, or l-methedrine.

Any info on the chirality of OTC ephedrine is necessary to anyone attempting hydrogenation, because the disire product is determined by the catalyst's ablity to hydrogenation with or without inversion of chirality

Hive Bee   posted 10-19-1999 07:09 PM          
If I'm understanding psychokitty, he is saying that the acetic ester of,... ephedrine? Or is he specking of something else? I'm lost as to what he is talking about. Phenylaniline? Help me out...

Wizard X
PimpBee   posted 10-19-1999 09:25 PM          
I can tell you with absolute certainty that
highly acidic conditions + heat induces rearrangement

PimpBee   posted 10-19-1999 10:09 PM          
Yes, psychokitty was talking about the acetyl ester of Ephedrine.

K.C. Nicolaou
Hive Bee   posted 10-20-1999 12:49 AM          
Since psychokitty asked for comments, here are mine.
Based on the info posted from the article, it seems that the basic gist of the article is that under microwave radiation, you get the following transformation.
NH4CHO2 + hydrogenation catalyst --> NH3 + CO2 + catalyst with adsorbed H2

The usefulness of this method then is primarily as an alternative to using H2 gas in catalytic hydrogenations. In this case, the method is nice because it avoids the hazards of H2 gas (pressure, flamability, etc) and could be put to very good use in the hydrogenolysis of benzyl esters or alcohols (conversion of ephedrine to ----) or the reduction of nitrostyrenes. Unfortunately, I think that the fact that a high-boiling solvent like ethylene glycol has to be used is going to make work-up a bitch. The only easy way I can think of to get rid of it would be to dissolve the rxn mixture in a non-water miscible sovent and wash the ethylene glycol out with water washes, which may lead to some loss of product in the H2O/ethylene glycol mix and might make catalyst recovery impossible or inefficient. However, it remains to be seen whether or not that would make this procedure less desirable than catalytic hydrogenation in larger reactions.

As for the reduction of phenylhydrazones to amines that you talk about, you don't really specify whether this results in the primary amine or the reduction of the hydrazone to the 1,2 disubstituted hydrazine.
If it is the primary amine, that's pretty cool, because you might be able to take a crude mixture of ketone straight from your rxn, add phenylhydrazine, collect the crystalline(hopefully) phenylhydrazone, and get amine without distilling in a very short amount of time . But, aside from the fact that phenylhydrazine is fairly nasty stuff, it seems to me that this may just be a microwave version of the leukart(ammonium formate anyone?) and the Pd catalyst may not do anything. If you have any info as to which amine you get, why the hydrazone was prepared instead of another imine(I can imagine a mechanism where the double bond in the phenylhydrazine undergoes a rearrangement that puts it in between the two nitrogens, and the N-N double bond is reductively cleaved through Pd-catalyzed hydrogenolysis, giving the primary amine and aniline), or any other info on the mechanism of this reaction, I would appreciate if you could post it.

All in all, good work pschokitty!!! 

Cherrie Baby
Hive Bee   posted 10-20-1999 01:14 AM          
There are a number of safety concerns about using microwave ovens:
Don't let the microwaves escape - don't need to worry about this unless you start messing about with your oven - chefs are often keen to have nothing but the best ovens.
Don't put metals in the oven - they will cause arcing. - which means sparks and fire.

Unmodified ovens are good but modified ovens are better.

"Design and application of a reflux modification for the synthesis of organometallic compounds using microwave dielectic loss heating effects". - Journal of Organometallic Chemistry, 384 (1990) C57-C60. - This article details a modification of a domestic oven to carry out reflux.

More interesting is "Microwave Dielectric Heating Effects in Chemical Synthesis" by Michael Mingos and Gavin Whittaker (who has a microwave chemistry site). This article is in a book "Chemistry under Extreme or Non-Classical Conditions", Wiley, 1997, ed. by Rudi van Eldik and Colin D. Hubbard. This goes into great detail on how to modify a domestic oven to make a mono-mode oven - recommended for DIY freaks, electronic gadgetissimos and perfectionist-chefs everywhere.

K.C. Nicolaou
Hive Bee   posted 10-20-1999 01:26 AM          
Ahh... sorry.
I just re-read the original post and looked a little bit closer at the actual numbers for the phenylhydrazone --> amine process. What I noticed was that at the dilution you described, you would need 1.4L of ethylene glycol per 100g of ketone, along with 30g of 10% Pd/C. That really sucks. Now, I realize that when people publish stuff like this, they aren't neccesarily trying to use the actual minimum amount of solvent per amount of reactants (especially not at the 2 mmol scale), so hopefully the amount of solvent and catalyst could be reduced without a significant loss in yield. Also, I have some concerns about the maximum batch size one could run in a single microwave and the limitations to overall efficiency (g amine produced per hour) that this, along with the removal of ethylene glycol, would cause (I know it's more than 2mmol/4min, but how much more?). Not to knock the potential of this method in any way, but it seems to me that it needs some serious work before it is ready for large scale production (seems great for small scale though).
Also, if the mechanism for the transformation of the phenylhydrazone to the primary amine is the one that I described in my previous post, then it should be possible to prepare the phenylhydrazone and convert it to the amine under regular catalytic hydrogenation conditions with Pd/C, which would be the first real way that I have seen on this site to get a useful amount of amine from a ketone using Pd as a catalyst. Someone should do a reactant/product search on Beilstein to see if that is a known reaction (I'll see if I can, but I don't know if I can do that kind of search with the Beilstein access I have).


PimpBee   posted 10-20-1999 02:03 PM          
Okay, here's my attempt at clearing up some of the questions you all have about the process:
1. Recovery of the final product would in all likelyhood be simple. First, the catalyst would have to be removed through decantation of the solvent followed by subsequent washes with ethylene glycol or possibly even some other suitable solvent. As long as the catalyst isn't allowed to completely dry, I'm sure even vacuum filtration can be made to work as a means of effecting its removal. Consider those hydrogentations that KrZ and several others have performed. I don't believe the pyrophoric nature of Pd/C ever really was considered to a serious problem (i.e, it doesn't seem to be THAT great of a hazard).

As for the extraction of the final product from the ethylene glycol solution, just dilute with water and extract with ethyl acetate or some other suitable solvent (just as they say to do in the paper). Really, I don't believe this part of the process can really be construed as a stepping stone to success.

2. As for the change in chirality of say using o-acetyl ephedrine or o-acetyl pseudoephedrine in this reaction, I don't see why it would happen. It doesn't happen in any Pd/C hydrogenation that I've ever read about so why should it happen during the course of this one? Besides, the reaction conditions aren't very acidic, or so it seems to me.

Anyone else have anything to offer as a way of clearing up this issue?

3. The end product of the reduction of the hydrazone is the primary amine (the paper specifies this). So, if one were to hypothetically use MD-P2P and covert it the the phenylhydrazone, and the reduce, the end product would be MDA. As for the question of the leukart reaction taking place, I'm not sure. I do know of a previous thread wherein the authors of some paper using ammonium formate and a ketone together ONLY, managed to form the N-formyl amine under microwave irradiation very easily and in a very short period of time. But the microwave CTH reaction uses dilute solutions and while the ketone is indeed used in the initial hydrazone formation stage, only the hydrazone itself is exposed -- in the SECOND stage -- to the ammonium formate and Pd/C.

4. Rhodium: I checked the profile of phenylhydrazone again using the Merck Index and an old copy of an Aldrich catalog. It is listed as a cancer suspect agent but the information I found does not indicate that it is in any way near as poisonous as, say, sodium cyanide or sodium azide. It is listed as being corrosive, however. But if one were to compare exposure hazards of one chemical to the next, well, chromium trioxide is listed as being a cancer suspect agent AND a HIGHLY toxic substance, yet I've gotton it on my hands so many times and never had to deal with even the slightest damage (that I know of).

Maybe phenylhydrazine is not as dangerous as one might assume at first . . . just don't drink any folks . . .

5. Yes, under standard CTH conditions, Pd/C and ammonium formate in refluxing ethanol can be used to reduce hydrazones to amines (there are several references listed in the title paper).

6. As for using modified microwave ovens, the authors of the paper show little preference to it. They even comment that although other labs succesfully control potential runaway reactions through such modifications, they wanted to make unmodified microwave ovens useful since they would likely be the kind most accessible to high schools and other small institutions (like us).

BTW, I almost forgot to mention that I was looking over the contents of the article last night and noticed one interesting little valuable piece of information that I omitted from my original report:

Experimental model --26 (the acetyl ester) was reductively cleaved in 90 SECONDS, not in ten minutes or so.



Hive Bee   posted 10-20-1999 07:35 PM          
Chem Guy why would not the use of the Urushibara catalyst not provide an improvement as regards safety to this process??

PimpBee   posted 10-20-1999 08:12 PM          
I take that back. I just did some more research. Phenylhydrazine is indeed VERY toxic and dangerous to handle.
Oh well.


Hive Bee   posted 10-20-1999 09:02 PM          
Psychokitty, here's my knowledge base on the subject of Pd inversion, (But not solely limited to this, I have other references)
From "Catalytic Hydrogenations over Platinum Metals", by Paul N. Rylander, 1967, page 321

A solution of 82.6 gm of l-ephedrine (XXVI) in 250 mL of absolute alcohol was reduced to XXVII without change in rotation over 1.6 gm ruthenium dioxide at 1200 psig and 90 C in 40 minutes (Freifelder and Stone, 1958). Hydrogenation over pallidium black was accompanied by reversal of rotation and..."

From "Practical Catalytic Hydrogenation; Techniques and Apllications", by Morris Freifelder, 1971, page 399-400

"The use of pallidium catalysts may be contraindicated in the hydrogenolyses of optically active, unsymmetrically substitued benzyl alcohols, esters and ethers if retention of configuration is desired. Palladium causes inversion; hydrogenation with nickel, copper, and cobalt catalysts favor retention ofconfiguuration."

Wizard X, I don't think that Highly Acidic conditions rearrange the amine chirality. I do know that they change the hydroxyol chirality of a compound. For instance HI + ephedrine --> ido-pseudoephedrine + H2O
Do you have any refences to support your claim. Personally I have never found a reference to amine rearrangement in highly acidic conditions.

(Llyod), Yes I do think that the urushibara nickel would be a great substitue for the Pd. In the thread called: What is the chirality of OTC pfed? - snow white states a reference which states that ephedrine in the US for clinical purposes is (+)-pseudoephedrine and (-)-ephedrine, which when subject to HI/RedPhosphorus reduction yeild d-methedrine. And since I'm pretty dam sure that HI/RedPhosphorus method doesn't cause amine chirality reversal then the Pd would cause reduction of (+)pseudoephedrine and (-)ephedrine into l-methedrine.

I went to the library today and photocopied the article, It is a sweet find. And as an answer to my previous question of options for other hydrogen donors. The article lists these possible hydrogen donors: "cyclohexane, hydrazine, fromic acid, ammonium formate, cyclohexdiene, and phosphinic acid, sodium,hypophosphite."

Hive Bee   posted 10-20-1999 09:24 PM          
Also, on the Rhodium site, cherrie baby states tha sodium formate works as well. I just don't see how, I wish that cherrie baby would post the mechanism.
Formic acid donates hydrogen like so:
H(C=O)OH (catalyst)--> O=(C=O) + nacsent hydrogen

Sodium formate: ?

I need some help here,

K.C. Nicolaou
Hive Bee   posted 10-20-1999 11:31 PM          
Psychokitty - Thanks for adressing my questions. I appreciate that. The numbers of the following responses correspond to the numbers in your last post.
1. I understand that you believe that final product recovery will be easy, but I have to disagree with your dismissal of this as a factor in the viability of this technique. If you've ever tried to get a reaction product out of dilute DMSO solution, you would know what I mean. For example, if you had 100g of final amine in 1.4L of Ethylene glycol and added 1.4L of EtOAc and 1.4L of H2O, you would probably end up with a homogeneous solution due to the fact that the ethylene glycol is going to be miscible with the aqueous and organic layers. Not to be a naysayer, but I think that diluting with water and extracting with an organic solvent would be a royal pain in the ass. However, it seems to me that an easy way out of this problem would be to add an amount of HCl sufficient to protonate all of the amine product present, vaccuum distill most of ethylene glycol off of the amine salt (save and reuse the solvent, although it could have some formic acid in it that needs to be removed), dilute in water, filter off the catalyst (save and reuse), wash the aqueous layer with organic solvent to remove neutral impurities, basify, and then extract the freebase into organic solvent. Since there may be some ammonia with the freebase at this point, a few water washes may be in order before HCl salt formation. Obviously, that procedure depends on a few assumptions, but I think it would probably work fairly well and allow reuse of solvent and catalyst.

2. Everything I know about Pd hydrogenation catalysts says that inversion of the nitrogen-bearing stereocenter can't happen, and the same goes for acid-catalyzed rearrangement. A possible source of confusion about this issue may be because when you go from starting materials with two stereocenters and then remove one of them, the specific rotation of the molecule is going to change (the +/- sign may even change), even though the chirality of the nitrogen-bearing stereocenter is unchanged. I could be wrong though.

3. Thanks, that answers my question completely. As a side note, if the microwave leukart occurs in this system, it would give the disubtituted hydrazine, which is also an intermediate in the hydrogenation pathway, and would get reduced by the Pd/C/H2 to give the primary amine just the same, so it really wouldn't effect the final product . As an additional note of speculation, it may be possible to produce the N-methylated derivative through the following sequence:

A. Combine the ketone and N-methyl benzylamine(could easily be made from MeNH2 and benzyl bromide) in toluene or benzene. Reflux using a Dean-Stark trap until all water is removed. The product will be the N-benzyl-N-methyl enamine.

B. Use this enamine in lieu of the hydrazone in the hydrogenation procedure(microwave or otherwise). Pd catalysts should be able to reduce both the C-C double bond and the benzyl-N bond. If the carbon-carbon bond is reduced faster that the benzyl-N bond, the N-methylated amine should be the only product. I can think of reasons why either of these bonds may be reduced faster than each other, but I think it would go in the order we want.

4. It's icky. Trust me. But probably not enough to keep anyone from using it .

5. Neat-o, I never knew that.

6. Don't know about all of the funky modifications cherrie baby is talking about, but a setup where you could reflux would be real nice, as it would allow the use of lower-boiling solvents such as MeOH, EtOH, and IPA.

CHEM GUY - Think of it this way... formate donates H-, giving CO2 as a byproduct, and the the H- combines with H+ from the protic solvent to give H2.

My two cents

... Fuck, TWO CENTS!!! I'm getting ripped off!!

K.C. Nicolaou
Hive Bee   posted 10-20-1999 11:52 PM          
Three things I forget in that last post...
1. Pd/C is a flame hazard because of two reasons. One is that the catalyst particles are really small in order to give a large surface area, making for a material very similar to coal dust. Now, as any miner will tell you, when coal dust and air get mixed, you have a serious explosion hazard . The other reason is that at the end of the reaction, the catalyst has a bunch of adsorbed hydrogen, making it extra flammable. However, I use Pd/C all the time and I can tell you that there is no fire hazard whatsoever when the catalyst is wet, so it is fine to filter it as long as you don't let it dry out. All in all, it is not really that big of a deal as long as you are careful.

2. In the hydrazone process, you have aniline as a byproduct that you need to get rid of at some point. Aniline's acid/base and solubility properties are similar enough to MDA's that distilation may be the only way to get rid of it. And you definitely need to get rid of it, it's not good for you.

3. Let's not forget what may be the real sleeper application of this technique, which is reduction of nitrostyrenes. Can you say mescaline, 2-CB, TMA-2, etc without LAH or H2? Yippie!!!

Hive Bee   posted 10-21-1999 12:00 AM          
K.C. Nicolaou, Thank you for enlightening me on the NaOCOH (sodium formate) hydrogen donor process. It is much appreaciated.
I do however wonder why you are doubting the texts to which I've quoted here. Unless I'm understanding them incorrectly they clearly state that Pd will cause inversion of the side chain of a molecule like ephedrine. Am I understanding them wrong. The first text directly references the reduction of ephedrine...


2 C2H5OH + 4 Na(OCl) --> CHCl3 + 3 Na(O[CO]H) + NaCl + 4 H2O

Na(O[CO]H) + catalyst and CTH conditions ---> nacasent hydrogen + Na(+) + CO2

K.C. Nicolaou
Hive Bee   posted 10-21-1999 12:59 AM          
CHEM GUY - It's not that I don't believe that you have books in front of you that say that, it's just that I have a hard time understanding how that could happen. I have had numerous experiences that have taught me not to believe everything I read, even scientific literature. If I did believe everything I read, I wouldn't even be here, cause most people that write about drugs say that drugs are bad, mmkay? I can't remember ever reading anything from you that sounded like bullshit to me(which is saying something, considering the forum), so don't take it personally when I don't believe this. Specifically, my reasons for disbelief are as follows:
1. To give inversion of the stereocenter attached to nitrogen, that carbon's C-H or C-N bond would have to be broken. I see no way that either of these bonds could be broken under the reaction conditions we are talking about. The only mechanism of inversion of stereochemistry I can even remotely imagine is H2SO4 catalyzed dehydration/hydration of ephedrine, which would give racemization, not inversion. I can't even imagine a way that Pd could do this in my wildest flights of fancy, which is saying a lot.

2.If what you are describing did happen to a significant extent, I think that everybody and their mother would know about it. Think of all those references by guys like Fester and Popeye about reducing acetate esters of ephidrine or psuedo-eph with Pd to give ----. If this gave the inactive isomers, don't you think that people would know about this and call bullshit on those guy's methods?

3. I just went back and read the part of the reference you quoted. If you look closely, it seems to me that the author is probably talking about inversion of stereochemistry at the BENZYLLIC CARBON (this can only happen if the benzyl position in the starting material doesn't have a hydrogen attached), in which case I have no trouble understanding how that would happen. However, this does not apply to ---- synthesis, as the product does not have a stereocenter at the benzyllic position, and in this case, reduction gives good ----, not bad.

By the way, have you confirmed that your chloroform/formic snth works by actually doing it? I could see it working like you say, but I can also see it giving CHCl3 and CO2.

All said, I think that you may be misinterpreting that reference, not that I haven't ever done that a few dozen times or so .

Hive Bee   posted 10-21-1999 01:17 AM          
I do understand what you are saying about Pd ablity to reverse the amine chirality, but I find it very difficult to misinterpet the text which directly deals with l-ephedrine and how Pd effects it by "reversal of rotation". Now the only rotation on a methedrine molecule IS the amine's chirality. It leads me to believe that our ignorence, or misunderstanding of the mechanism is only due to improper schooling and or textbooks.
The NaOCl and ethanol reaction was lifted from literature: "Organic Chemistry", 6th Ed, Edited by F Dergering, Ph.D, yr 1957, page 303, But they listed this reaction:
4 C2H5OH + 8 Ca(OCl)2 --> 2 CHCl3 + 3 Ca(O[CO]H)2 + 5 CaCl2 + 8 H2O

I just change the Ca for Na and did the math. I just thought more people would have a better grasp of it if I use common bleach instead.

This thread is going to change the world I tell you...

K.C. Nicolaou
Hive Bee   posted 10-21-1999 11:50 AM          
Chem Guy - I guess we'll just agree to disagree. I'm not really well schooled in which stereoisomer of ---- is the good one or what the absolute configurations of commercially availiable eph/psuedo-eph are, so I can't really say what's going on just by looking at your reference. However, I will say that that fucking l,d isomer bullshit can be confusing as hell, because in some cases(like amino acid nomenclature) l=S and d=R, and in others, l=levorotary=the sign of the measured optical is negative and r=the sign of the measured rotation is positive. Since this is an old reference, I would suggest that you try and figure out the exact configuration of the N-bearing sereocenter in both the starting material and the product. Also, since it is a fairly old reference, you might want to try and find mention of this phenomena from another source. If one source tells me something I may have trouble believing it, but if two or three independent sources are telling me the same thing, I generally have a real hard time NOT believing it, and in this case, all of the other info I have tells me your source is incorrect. Or, you could always just verify it through experiment.

Hive Bee   posted 10-21-1999 02:30 PM          
The issue has never seemed that critical to me: seems like many people have commented on the desireability of product with both configurations anyway.
Some fine stuff has been derived by those who have chosen natural ephedrine as a starting point, which will give you some of both:

KRZ's (I believe) experiment described using hydrogen @ 30 PSI, 20 ML sulf (30%), in 800 ML EOH, Pd/c , vigorous stirring, 60 deg C,
and starting with extract of ephedra: precipitated (86% yield) the best stuff ever seen: thus illustrating the point, at least in my own mind.

Let's get some results and quibble over details later!


Wizard X
PimpBee   posted 10-21-1999 08:33 PM          
Phenylhydrazine is indeed VERY toxic and dangerous to handle. It also makes a great explosive when reacted with HNO2.
Anyway, Phenylhydrazine + P2P gives a 99.5% condensation product, "hydrazone". Electrochemical reduction, Raney nickel or Pd & Pt catalytic reduction will reduce the hydrazone to an amine.

Wizard X
PimpBee   posted 10-21-1999 08:41 PM          
BTW psychokitty good work. Credit is due on this find.

Hive Bee   posted 10-21-1999 11:23 PM          
This chirality shit is getting very confused.
D (upper case) and L (upper case) are used in carbohydrate and amino acid chemistry.
d (lower case) and l (lower case) are NOT the same, meaning dextrorotary and laevorotary, or (+) and (-) optical rotation of plane polarized light. D is not d, L is not l.
Absolute configuration is not optical rotation. Absolute configuration, if using Cahn Ingold Prelog convention to specify:
D = R & L = S
The only way to find out if, for instance, the R enantiomer is (+) or (-) is by using a polarimeter.
In the article I posted under thread "Phenylalanine synth" (which should have read "---- synth from phenylalanine") Dextroamphetamine (d-amphetamine) is this:
---- is given as:

Hence d----- ( + ---- or dextrorotary) is (S) configuration.

PimpBee   posted 10-22-1999 03:21 AM          
K.C. Nicolaou: you mentioned CTH reduction of nitrostyrenes. As far as I know, CTH reduction doesn't work well (at all?) for this class of substances. At least that's what a ref said.

Hive Bee   posted 10-22-1999 05:52 AM          
In Rhodium's page there's a reduction method using CTH, am. formate and formic acid, and it works in 30 minutes or so using standard heatind at 100-110 C, basically it's the same procedure, so I don't see any advantage in this method, due you must control the temp opening the microwave and checking it, what is obviously more complicated than to put a thermometer in the rxn flask.

Hive Bee   posted 10-22-1999 03:48 PM          
Is D Dextro? Is L Leo?
One thing that I know is that the microwave can be our best friend. Looks like if we can do this proceedure this will be a great Hive Post. Seems like you can run four 2000 ml. Flask all at the same time. I wonder what would be a good tempature indicator to use while the microwave is is running? It is kind of lousy haveing to open the door to measure tempatures. But at least it can be calibrated according to power levals.

Live With Freedom

K.C. Nicolaou
Hive Bee   posted 10-22-1999 08:18 PM          
Osmium - I don't know for sure(personal experience or good literature references), but hydrogenation of nitrostyrenes has been reported by drone 342(Rhodium's site) and KrZ(I think) as a route to make mescaline. Theoretically speaking, I can see two completing outcomes in hydrogenation of nitrostyrenes.
1. Clean reduction to the amine.

2. Reduction of the nitrostyrene to the enamine, followed by rearrangement to give the imine, which will not get reduced by H2 and Pd/C and will give the ketone upon acid hydrolysis.

If you post your reference, I'm going to be in the library this weekend and I'll try to photocopy the artilcle/book and tell you what I think.

K.C. Nicolaou
Hive Bee   posted 10-22-1999 08:22 PM          
That's article, not whatever I just wrote

In the microwave variant,if 2 happens and there isn't much water present, the imine might get reduced to the amine by the ammonium formate present(microwave leukart).

PimpBee   posted 10-23-1999 04:10 AM          
I'll try to find it.

Hive Bee   posted 10-29-1999 06:26 PM          
I say, was hasn't anyone done anything else on this thread?
This is a perfect Urushibara catalyst canidate. Add the preceptiated nickel into the ethylene gylcol with 5 equivalents of NaOCOH and mircowave the fuck out of it. Hydrogenolysis? I'm pretty sure,...

PimpBee   posted 10-30-1999 11:22 AM          
I found the article, but of course don't have it with me. Silly me.
It's a review about ammonium formate CTH reductions. They claim it didn't work very well for nitrostyrene and relatives, low conversion.

Hive Bee   posted 11-01-1999 01:05 PM          
Nobody would or should there is an easy way

Hive Bee   posted 11-01-1999 01:07 PM          
PK is gona do it????

Hive Bee   posted 11-01-1999 01:08 PM          

Hive Bee   posted 11-02-1999 01:23 PM          
What the hell are you talking about? If you have something on the subject to contribute, do so, but if you are just going to fill the thread up with stupid one liners you'll bee hard pressed to get any responses when needed

Hive Bee   posted 01-24-2000 07:39 PM          
OK I'm going back and forth between this thread and http://hive.lycaeum.org/ubb_board/Forum5/HTML/000683.html 
The Gemini bottle may be a help here inasmuch as the temperature can be inferred by noting when the (whatever pressure you choose) popett valve starts letting out pressure. (For sake of discussion, a 20 PSI pop off valve)

The gas will be retained by the balloon surrounding the valve stem: but the beginning of it's inflation will be your hint to stop. (and cool off  )

I can't get around the "flat bottomed vessell" requirement: but wonder just how important that would be: seems like the liquids would have a pretty good thermal mising going.....


Hive Bee   posted 01-27-2000 09:28 PM          
make shure it runs on its side first then just leave the door open or remove the door and lay it down on the counter top,,, it should only take a few seconds howver the necessary technology has not been eluded to at all....
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rennie coombs

Joined: 22 Jun 2005
Posts: 2
Location: australia
58.26 Points
re: Microwave-Assited Rapid and Simplified Hydrogenation

Sat Sep 10, 2005 11:28 am

Have read posting on L-pac to e.... I can see that this was early this year but it has taken a little time.. Could you run some quantities for microwaving? And some ideas of recovery from solvents. Can try some. thks
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Joined: 07 Feb 2005
Posts: 736
Location: The Mexican Republic
21794.14 Points
re: Microwave-Assited Rapid and Simplified Hydrogenation

Sat Sep 10, 2005 8:11 pm

The quantities should be the same as for the hydrogenation of ephedrine as mentioned my psychokitty ans keeping in mind the problems of the removal of the ethylene glycol brought up by K.C. Nicolaou. This procedure is good for small quantities as the removal of the solvent (ethylene glycol) makes it troublesome for large quantities.................java
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Table of Contents

I. Introduction

The clandestine manufacture of drugs can be defined as the illegal manufacture, compounding or processing of narcotic, stimulant, hallucinogenic or depressant drugs. Prior to the 1960's the major drug clandestinely prepared was heroin (diacetylmorphine, Fig 1). Through the 1960's the manufacture and use of hallucinogenic and stimulant drugs began to increase1 and it was necessary to enact the Controlled Substances Act to control the manufacture and distribution of illicit drugs.1 Even with these controls, an active underground pharmaceutical industry continues to supply controlled and novel substances to the illicit drug market2,3. The quality of the manufacturing personnel within this industry ranges from individuals with no training in chemistry that follow "cookbook" directions, to chemists that appear skilled in drug design and synthesis attempting to keep "ahead of the law by developing new compounds or by changing the molecular structure of existing ones."1 The various approaches to the synthesis of various classes of novel drugs of abuse has been earlier outlined4 and the extent to which the clandestine pharmaceutical industry has succeeded is one aspect of this review.

Another problem related to clandestinely prepared drugs is the quality of the drug formulation finally sold on the "street." Clandestine laboratories do not generally follow current good manufacturing practices (CGMP) and the material used on the street is frequently impure as well as being misbranded and adulterated. The additional substances present with these drugs can be classified as diluents, adulterants, impurities of manufacture and impurities of origin.5,6 Due to the multitude of drug combinations sold in the illicit drug market only the last two classes are discussed in this review since they are characteristic of the synthetic route used in the manufacture of the drug or class of drugs.

Most reports which identify new illicit drugs or impurities are from the forensic drug chemist, primarily because the forensic chemist receives more samples and greater quantities of material than received in a clinical or hospital toxicology laboratory. Within the United States much of this work is done by the Drug Enforcement Administration (DEA) which contains a strong research component consisting of synthetic chemists, analytical chemists, pharmacologists and field investigators trained in chemistry. Comparable forensic laboratories in other countries are also actively involved in identifying the composition of illicit drugs. The occurrence of impurities of manufacture or precursors of origin is of considerable importance to the forensic drug chemist since it provides information as to: 1) whether the drug is clandestinely made, 2) the synthetic route, precursors and reagents being used, 3) the reaction conditions or apparatus necessary for the synthesis, and 4) whether two samples are coming from the same or different laboratories. This synthetic information aids in the investigation and provides evidence during prosecution. This also allows the forensic chemist to anticipate what hazardous conditions may exist when closing a clandestine laboratory (this sometimes occurs under less than friendly conditions). The occurrence of these contaminants have also been of interest to toxicologists, medicinal chemists and pharmacologists since they may modify or enhance the activity of the "parent" drug or may exhibit an activity or toxicity unrelated to the "parent" drug. The dissemination of information about these new drugs in the illicit drug market as well as the pharmacology/toxicology associated with these compounds is an important responsibility placed on the DEA.1 Since the time necessary for normal modes of publication of this information is quite lengthy, the DEA edits and publishes a monthly newsletter entitled "MICROGRAM" which is "restricted to forensic scientists serving law enforcement agencies." This newsletter contains reports from forensic drug laboratories throughout the United States and, occasionally, from international sources with emphasis on drugs and novel analogs currently present in the illicit drug market as well as incidence and extent of impurities of origin and manufacture. The DEA has chosen to control dissemination of this information since practical information that would be of considerable use to clandestine drug manufacturers is also frequently included. Most observations of new or unusual compounds initially appear as anonymous reports which are later followed by separate reports which provide spectral characterization of the chemical for use by the forensic chemist.

Some of the information discussed in this review was originally reported in MICROGRAM and is not available in the open literature. Therefore, when the original authors have published reports in both MICROGRAM and the open scientific literature, only the latter will be cited.

In this review the general classes of clandestinely synthesized drugs are divided into narcotics, stimulants, hallucinogens, dissociative anesthetics and depressants. Each class is then divided into the major synthetic methods for the class of drug (including analogs), occurrence of synthetic impurities and the pharmacology/toxicology associated with the analogs and impurities.

II. Narcotics

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A. Heroin

Figure 1
Opium derived contaminants present in heroin


Until recently the only source of heroin (diacetylmorphine, Fig 1) in the United States was by clandestine synthesis, which was usually done outside the United States. The synthesis is easily accomplished using acetic anhydride or acetyl chloride to acetylate morphine isolated from opium.7 However, depending on what extent the morphine has been purified from the opium prior to synthesis, the resulting "heroin" will contain additional alkaloids and impurities. Continued efforts by the forensic chemist have been directed toward identifying and quantitating these impurities of origin present in heroin. Currently heroin is classified as coming from three major areas of the world and the heroin from these areas is named Southwest Asian (SWA) heroin, South-east Asian (SEA) heroin and Mexican heroin with further subclassifications based on physical appearance and impurities. Throughout this discussion heroin will indicate the crude mixture of alkaloids obtained by acetylation of opium or partially purified opium and diacetylmorphine will indicate pure drug.

The impurities expected to be present in diacetylmorphine are 6-monoacetylmorphine (6-MAM) and morphine. The extent to which these contaminants occur is dependent on the care/skill used in working up the acetylation reaction and preparation of the salt, as well as the conditions under which the heroin is stored prior to its use. As shown in Table 1 the occurrence of 6-MAM in illicit heroin is highly variable with many samples consisting primarily of 6-MAM and morphine.

Table 1

Trimmed Mean of Alkaloids in Illicit Heroin

In addition to morphine, crude opium obtained from Papaver somniferum contains over 25 additional alkaloids. These are divided into the five "chemical" groups: 1) phenanthrene, 2) benzylisoquinoline, 3) tetrahydroisoquinoline, 4) cryptopine and 5) alkaloids of unknown structure. Morphine is included in the phenanthrene group along with codeine and thebaine. Additional alkaloids which are present in relatively high concentrations are cryptopine and the benzylisoquinolines papaverine, noscopine (narcotine), laudanosine and narceine.19 Depending on what extent morphine is purified from the opium prior to acetylation these naturally occurring alkaloids or their acetyl derivatives would be expected to be present. As early as 1962, Nakamura and Ukita20 suggested that acetylcodeine was present in illicit heroin to the extent of approximately 10%. As analytical methodology improved the detection of acetylcodeine in illicit heroin was commonly observed.4,9-12,15,16,21-25 In the studies in Table 1 in which acetylcodeine was quantitated, its concentration relative to diacetylmorphine on a molar basis is usually 10�20% and ranges up to 45%. Although this implies an original concentration of codeine in opium which seems relatively high compared with codeine concentrations reported in many standard texts,26,27 the concentration of codeine (including very high concentrations) is in reasonable agreement with levels of codeine found in United Nations reference capsular tissue of P. somniferum17 and in Indian opium.18 Studies are very limited in which the alkaloids papaverine, laudanosine, cryptopine and noscopine have been reported.12,15,16,24,25,28-30 In the quantitative studies of these alkaloids in illicit heroin (Table 1),12,15,16 both papaverine and noscopine were present in much lower concentrations than expected based on their concentration in crude opium. It would appear that these alkaloids are either removed during purification of morphine and/or undergo some type of reaction (decomposition) during the acetylation procedure. The fact that thebaine is rarely if ever observed in illicit heroin is attributed to its decomposition during acetylation since thebaine readily decomposes in the presence of anhydrides, acid chlorides or strong mineral acids.31,32 Two decomposition products of thebaine have been identified in heroin. These are 3,6-dimethoxyphenanthrene-4,5-epoxide and 3,6-dimethoxy-4-acetoxyphenanthrene (acetylthebaol).15,32,33

Acetylthebaol concentration ranged from 0.003 to 0.33% in 56 samples of heroin.14 To what extent other opium alkaloids are transformed to new products under acylation conditions similar to those used to prepare illicit heroin, has not been reported.

Small and coworkers33 originally reviewed and compared the pharmacological activity and toxicity associated with the diacetylmorphine impurities morphine and 6-MAM (Table II). It was seen that the activity of diacetylmorphine and 6-MAM closely parallel each other with 6-MAM being slightly more active. Both compounds were from 2 to 10 limes more active than morphine depending on the pharmacological effect being evaluated. Recent work continues to confirm these original results.35 It is currently accepted that the activity associated with diacetylmorphine is due to its metabolic hydrolysis to 6-MAM and morphine which are the active forms.36 Although it may be anticipated that the pharmacodynamics or pharmacokinetics of diacetylmorphine and 6-MAM might be different, this has not been observed in behavioral studies following subcutaneous administration in mice35 or in metabolism studies following intravenous administration in dogs.37 Therefore, the pharmacological effects expected from a sample containing both diacetylmorphine and 6-MAM would be comparable to an equimolar sample of pure diacetylmorphine and the quantity of both present would most accurately reflect the strength of an illicit heroin sample.

Table II

Pharmacological Effect* of Morphine Based Alkaloids34

















































* �moles of alkaloidal base per kilogram

  1. Average fatal dose, amount killing 50% or more of animals following subcutaneous injection
  2. Smallest amount with which convulsions were observed during toxicity test
  3. Smallest dose preventing immediate righting of >75% of a group of 20 rats, 30 min after i.p. injection
  4. Amount of drug administered intramuscularly which caused in at least 4 of 5 cats an increase in the
    pressure required to evoke a response when applied to the terminal position of the tail
  5. Smallest dose with which definite signs of exciting action were seen in at least two of a group of five cats
  6. Smallest dose with which a cat vomited
  7. Minimal effect depressant dose (minute volume)
  8. No effect at dose tested
  9. Not reported

Additive analgesic effects of the alkaloids in opium are reported to occur with crude opium, ie. 20 mg of the hydrochlorides of opium alkaloids with a morphine content of 10 mg of morphine (Pantopon�) is considered therapeutically equivalent to 15 mg of morphine.38 However, disagreement exists on this point.39 To what extent these additional alkaloids or their acetylation products could modify the pharmacological effect of crude heroin does not appear to be an area of recent study. As shown previously the major impurity of origin in heroin is acetylcodeine. In Table II are the results of the animal studies comparing codeine and acetylcodeine to diacetylmorphine, 6-MAM and morphine as originally reviewed by Small and coworkers.34 What is quite unexpected is the toxicity and convulsant activity of acetylcodeine. In the mouse model it was two times more toxic and three limes more active as a convulsant than diacetylmorphine. Based on the common occurrence of acetylcodeine in heroin at relatively high concentrations it could contribute to its toxicity.

The other major alkaloids in heroin are the benzylisoquinolines. Papaverine has been used therapeutically as a nonspecific smooth muscle relaxant and as a coronary vasodilator. At relatively high intravenous doses (100�200 mg), papaverine causes cardiac arrythmias.40,41 Its intravenous LD50 in mice is 80 micromole/kg.42 Noscopine and laudanosine also have vasodilator activity. Noscopine is sold as an over-the-counter, oral, cough suppressant with no addiction liability. Unexpectedly, the toxicity of noscopine is comparable to codeine following subcutaneous administration to mice (LD50 of noscopine is 0.44 mmole/kg vs 0.25 mmole/kg for codeine).43 Cryptopine, when given intravenously to rabbits (8 ng/kg) is reported to cause mydriasis and a general disruption of motor coordination and posture.44 It is unclear if these additional alkaloids, especially at the lower concentrations observed in heroin (except for acetylcodeine) could substantially add to the pharmacology/toxicology of heroin.

Less information is available about the identity and pharmacological effects of the decomposition products formed from the materials present in opium following the synthesis of heroin. Acetylthebaol, derived from thebaine, has been evaluated in cats for its acute effect as an analgesic, general depressant, emetic and hypothermic agent, but was found to have slight to no effect in all of the tests.34 The toxicity or chronic effects of chronic exposure to acetylthebaol has not been reported.

That heroin containing these additional by-products and alkaloids may have an enhanced or different pharmacological profile than that attributable to diacetylmorphine and 6-MAM is suggested when comparing "street" heroin potency and deaths in different regions of the United States.45 In cities along the East Coast, where, primarily, a white and relatively pure form of heroin is sold, there is observed a statistically significant correlation between the number of heroin-related fatalities and the purity of the heroin available.46,47

However, in a comparable study in San Antonio, Texas, where a dark brown Mexican heroin prepared by direct acetylation of opium is prevalent, a non-significant correlation (r = +0.13) was found between potency of street heroin and frequency of heroin overdose.48 In the Texas study this low correlation was considered to be due to uncontrollable variables such as simultaneous use of alcohol and other depressants, hidden suicide and reduced opioid drug tolerance due to institutional treatment. The role of these additional contaminants was not evaluated. Since the method used to characterize the heroin during the study was not described, no further conclusion can be made on the importance of impurities of origin on the toxicity observed.

Figure 2
Synthesis of MPPP and MPTP

B. 4-Phenylpiperidines

A series of totally synthetic analgesics with abuse potential comparable to morphine are the 4-phenylpiperidines. The lead compound in the series, meperidine, is not known to be clandestinely manufactured. Its "reversed" ester, 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP), in which the carbethoxyl group in meperidine is replaced with the propionoxy group, has been used as a heroin substitute in the illicit drug market,49,50 as had been previously predicted.4 The use of MPPP is probably due to the facile synthesis of this compound as depicted in Fig 251 relative to that of meperidine. In the initial reports describing the synthesis of MPPP there was reported the formation of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) as a by-product of the synthesis. MPTP was formed during the reaction with the phenyl grignard, in the acylation step or if the intermediate alcohol was exposed to strongly acidic conditions. Due to the ease with which MPTP is formed it would be expected to be present in MPPP if inadequate sample purification occurs. Clandestinely manufactured samples were observed to range from 27% MPPP 12.5% MPTP (w/w) to 0.3% MPPP 13.2% MPTP.50

As previously stated MPPP is used as a form of "synthetic heroin." In animal studies, 1 mg of MPPP was equivalent to 25 mg of meperidine or 3 mg of morphine51 and at a dose of 3 mg/kg rats developed a catatonic state lasting about 1.5 h.49 The tertiary alcohol intermediates were evaluated and are reported to have slight activity and the tetrahydropyridine had "distinct" activity similar to morphine.51 In later studies MPTP was reported to have no analgesic or sedative effect in mice and was considered "extremely toxic" (LD50 about 150 mg/kg).52,53 No chronic studies with these agents were reported at that time. When a number of individuals repeatedly used MPPP contaminated with MPTP, symptoms characteristic of Parkinson's disease developed. It was proposed that MPTP was responsible for the Parkinson-like symptoms49,50 and this has been substantiated by the report that MPTP caused comparable symptoms in monkeys.54,55 Although usually the abuse of drugs is considered of little benefit to society, the discovery of MPTP may have facilitated the study of Parkinson's disease and is considered a major advance in the field.

Figure 3
Synthesis of fentanyl and analogs observed in the illicit drug market





















Fentanyl (N-phenyl-N-[1-(2-phenylethyl)- 4-piperidinyl]propanamide) is another modification of the meperidine structure which has been used as a "synthetic heroin." Clandestinely manufactured fentanyl has been observed based on the detection of norfentanyl (N-phenyl-4-piperidinyl-propanamide) in samples.56 Details of the licit or illicit preparation of fentanyl are not readily available. However, the proposed synthesis is depicted in Fig 3.57 During the synthesis of fentanyl, the acetyl analog, acetylfentanyl (N-phenyl- N-[1-(2-phenylethyl)-4-piperidinyl]- acetamide), can occur as a contaminant and is believed formed during the acylation of the anilino nitrogen with propionic anhydride contaminated with acetic anhydride.58 A second potential contaminant is the phenethyl quaternary salt of fentanyl which can be formed during the N-alkylation step. These compounds have not been observed in pharmaceutical quality fentanyl58 and have not been analyzed for in the clandestinely manufactured samples. Three analogs of fentanyl have been observed in the illicit drug market: α-methylfentanyl (N-phenyl-N-[1-(1-methyl-2-phenylethyl)-4-piperidinyl]propanamide),59 p-fluorofentanyl (N-(4-fluorophenyl)-N-[1-(2-phenethyl)-4-piperidinyl]propanamide)60 and acetylfentanyl.61 The clandestinely manufactured analogs are extensively contaminated with synthetic by-products and precursors. A sample of α-methylfentanyl contained 1.9% α-methylfentanyl�HCl, 0.6% propionanilide, 1.2% additional chloroform soluble compounds, and the remainder, lactose.62 In a separate study63 despropionyl-α-methylfentanyl was identified in the body fluids following an α-methylfentanyl death and its occurrence suggested it was in the original drug sample. In a sample of p-fluorofentanyl the intermediates shown in Fig 4 were reported identified.60 A sample of acetylfentanyl was also reported to contain acetanilide, acrylanilide and N-[1-(1-methyl-2-phenylethyl)-4-piperidyl]acrylanilide.61 Except for the first study on α-methylfentanyl no studies to quantitate these intermediates have been reported.

Figure 4
Precursors and byproducts present in a sample of p-Fluorofentanyl

Fentanyl, a drug used exclusively in the licit drug market for operating room anesthesia, can be used as a heroin substitute. It is pharmacologically equivalent to morphine except for its being eighty times more potent with a rapid onset and shorter duration of action.64 In mice, acetylfentanyl is 15 times less potent than fentanyl.65 The synthetic contaminants of fentanyl, N-phenyl-4-piperidinylpropanamide and the phenylethyl quaternary salt are not morphine-like and are atoxic at 40 mg/kg subcutaneously in mice (versus 15 microg/kg in mice for fentanyl).65α-Methylfentanyl, which is often referred to as "China white," has a short duration of action (90 minutes) and is approximately 300 times more potent than morphine in monkeys (ED50 of 1.6 to 6 microg/kg depending on the mouse test)66. Pharmacological effects for the remaining analogs and contaminants are not reported. However, it would be anticipated that the p-fluorofentanyl would have activity comparable to fentanyl.

As has already been observed, due to the high activity of the phenylpiperidines, accidental overdoses can easily occur. Too little is known to anticipate what effects would be observed following acute or chronic exposure to the numerous synthetic contaminants which occur in the 4-phenylpiperidine series.

III. Stimulants

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A. Phenylisopropylamines

Those compounds discussed as stimulants are amphetamine, its analogs, and cocaine. There are numerous methods reported for the synthesis of amphetamine. The major methods utilized by the clandestine chemists, using starting materials that can be easily purchased and/or the chemical operations required, are not very sophisticated. The major synthetic routes used in the clandestine synthesis of amphetamine have been recently reviewed.3,67 In the United States during the 45-month period prior to September, 1983, approximately 8-10% of the clandestine laboratories seized by the DEA were manufacturing amphetamine, while during the same time period, 40-55% were manufacturing methamphetamine.3 This contrasts with what was observed in the Netherlands in which 22 clandestine laboratories were manufacturing amphetamine and only one laboratory was synthesizing methamphetamine.67 The synthetic procedures used for amphetamine and methamphetamine as well as the impurities of manufacture present in the "finished" product do not completely overlap. Therefore, each compound will be discussed separately.

Figure 5
Commonly occurring synthetic impurities present in amphetamine
or methamphetamine prepared from phenyl-2-propanone

An important precursor common to both amphetamine and methamphetamine is phenyl-2-propanone (P2P, phenylacetone, methyl benzyl ketone). Until February 11, 1981 it was available commercially as a generally useful synthetic intermediate. Because of its facile conversion to amphetamine and methamphetamine it is now listed as a Schedule II-controlled substance and there are clandestine laboratories that now synthesize only P2P. In the review by Frank3 four major syntheses of P2P were reported. The most frequently used method (75%) is shown in Fig 5 starting with phenylacetic acid, acetic anhydride and sodium acetate or pyridine. Additional synthetic routes include reacting phenylacetic acid and acetic add in a combustion tube containing thorium oxide or manganese oxide catalyst (approximately 5%); reacting benzyl cyanide, ethyl acetate and sodium ethoxide to form α-phenyl-acetoacetonitrile followed by hydrolysis and decarboxylation (approximately 10%); and reacting benzaldehyde and nitroethane in butylamine to form 1-phenyl-2-nitropropene followed by reduction with iron and hydrochloric acid (approximately 4%). The most common synthetic by-product present in P2P prepared from phenylacetic acid is dibenzylketone.68 Impurities present using the other methods have not been reported. As expected, the ketones, P2P or dibenzylketone, are rarely observed in clandestinely manufactured amphetamines due to the use of amphetamines in the salt form.

In both the United States and the Netherlands the Leuckart reaction (Fig 7) was being used to synthesize amphetamine in 70-90% of the clandestine laboratories. Since the Leuckart reaction is often encountered there are several reports identifying impurities of manufacture. These impurities include synthetic intermediates as well as those associated with impure reagents. The only synthetic intermediate reported for amphetamine is N-formyl-1-phenyl-2-aminopropane (N-formylamphetamine).69 It has been detected in trace amounts and is due to incomplete acid hydrolysis in the final step. Of the strongly basic amines the anticipated by-product of the Leuckart reaction is successive reaction of amphetamine with P2P to form the secondary and tertiary amines,70 di(1-phenylisopropyl)methylamine and tri(1-phenylisopropyl)methylamine, The secondary amine has been observed in illicit amphetamine prepared via both the Leuckart route and by reductive amination using hydrogen and catalyst. The tertiary amine was also reported to be observed,71 however, the material believed to be the tertiary amine was incorrectly identified and was subsequently found to be the N-formyl derivative of the secondary amine, di(1-phenylisopropyl)formamide.72 It should be noted that di(1-phenylisopropyl)methylamine and its formyl derivative have two chiral centers. A diasteromeric pair and a meso stereoisomer are expected to be present and this has been suggested based on the GC and HPLC analysis of illicit amphetamine. The di(1-phenylisopropyl)formamide appeared as two peaks71,72 with the mass spectrum of each peak nearly identical.72

Figure 6
Weakly basic synthetic contaminants present in amphetamine
synthesized using the Leuckart procedure

Additional contaminants that are reaction specific for the Leuckart synthesis are the weakly basic amines. In Fig 6 are tri- and tetrasubstituted pyridines,73-75 pyrimidines76 and a dihydropyrid-3(H)-4-one77 which have been identified in illicitly manufactured amphetamine.

Impurities present in the starting material and reagents account for the remaining contaminants. The dibenzylketone in P2P will react with formamide in the reductive amination reaction to give the dibenzylketone amine counterpart of amphetamine, 2-(phenylmethyl)-phenylethylformamide (Fig 5). Acid hydrolysis gives 2-(phenylmethyl)phenethylamine69 which is commonly detected in illicit amphetamine. Formamide containing acetamide would account for 2,4-dimethyl-3-phenyl-6-(phenylmethyl)- pyridine73 identified. In the reports on these impurities there has been no quantitation of these contaminants.

Additional contaminants detected in illicit amphetamine include N-(1-phenylisopropyl) benzylmethylketamine,78 N-(1-phenylisopropyl)benzaldimine,78 N-acetylamphetamine and 1-oxo-1-phenyl-2-(1-phenylisopropylimino)- propane.79 These compounds are not considered to be route specific since they can be obtained by refluxing equivalent amounts of amphetaminne and P2P under dehydrating conditions.67

Figure 7
Clandestine methods used to synthesize methamphetamine

The major methods used to synthesize methamphetamine are shown in Fig 7. In the methamphetamine laboratories seized by the DEA in contrast to the amphetamine laboratories, only a small number (10%) used the Leuckart route.3 The most popular method (50%) and by far the easiest and cheapest is the reductive amination using P2P, methylamine, aluminum (from aluminum foil), mercuric chloride (catalytic amount) and alcohol.80 Due to the controls placed on P2P an increasing number of the laboratories are trying to synthesize methamphetamine using benzyl chloride, acetaldehyde and methylamine (10%). However, the synthetic protocol in the underground publication gives an incorrect sequence for addition of reagents, therefore, none of the laboratories using this method were successful in synthesizing methamphetamine.3 The remaining synthesis converts ephedrine to methamphetamine (10 laboratories) by reductive cleavage of the hydroxyl group. Finally, two laboratories have been found which simply extract l-methamphetamine from over-the-counter nasal inhalers.3

The synthesis of either amphetamine or methamphetamine from P2P, regardless of the synthetic procedure used, will give a racemic mixture. However, when using ephedrine as the precursor, its chirality will determine the chirality of the methamphetamine formed. Retention of configuration will be observed during the reduction and this has been verified in the conversion of phenylpropanolamine to amphetamine.81 Extensive reports characterizing the enantiomeric composition of illicit amphetamine or methamphetamine have not been reported. Analytical methods are available for characterizing each enantiomer. However, this is not routinely done by the forensic drug chemist since the law currently treats the d and I isomers of both amines as Schedule II drugs unless present in the appropriate drug formulation.

The impurities present in illicit methamphetamine have been thoroughly reviewed by Kram and Kruegel.82 In addition to discussing the impurities identified in the "finished" product they have also reviewed contaminants present in reaction mixtures obtained from clandestine laboratories.

The strongly basic impurities associated with the Leuckart route are the N-methyl analogs observed with amphetamine, N-methylamphetamine formamide83,84 and N-methyl-di(1-phenylisopropyl)methylamine.85 In 30 randomly selected samples, N-methylamphetamine formamide ranged in concentration from 10 to 39% (w/w) relative to methamphetamine.83 In a different study the concentration of N-methyl-di(1-phenylisopropyl)-methylamine in eight samples ranged from 3-15% relative to methamphetamine.85 Also, N-methyl-2-(phenylmethyl)phenethylamine is found and can be attributed to dibenzylketone present in the P2P.8 In two separate reports on illicit methamphetamine received in Texas, one sample contained 41% methamphetamine and 31% N-methyl-2-(phenylmethyl)phenethylamine86 and the other sample was 21% methamphetamine and 30% N-methyl-2-(phenylmethyl)phenylethylamine.87 In the Leuckart synthesis ammonia and N,N-dimethylamine may be present as contaminants in methylamine (formamide and N,N-dimethylformamide as contaminants in N-methylformamide). Therefore, the presence of N-formylamphetamine in methamphetamine can be readily explained and is specific for the Leuckart synthesis.82 Additional by-products which can be formed during the Leuckart route or by reductive amination due to these impurities include amphetamine, di(1-phenylisopropyl)methylamine, 2-(phenyl-methyl)phenylethylamine and N,N-dimethylamphetamine in low concentrations.82,88 In methamphetamine believed to be prepared by methods other than the Leuckart, methylamine and N-methyldiphenethylamine have been identified.82 In reaction mixtures obtained from clandestine laboratories, P2P, phenyl-2-propanol, formic acid, dibenzylketone and all the previously mentioned contaminants have been identified.82

The reductive amination procedure using an aluminum-mercury amalgam goes in extremely high yields and a very pure product can be obtained. However, inadequate purification at the final step can lead to an off-white or grey product containing mercury and probably aluminum. Samples from 15 of 25 methamphetamine laboratories were found to contain mercury ranging from trace levels (less than 0.1 ppm) to 1300 ppm mercury. The form of the mercury in the sample was not determined.89 There has been no comparable study to identify weakly basic amines formed during the synthesis of methamphetamine.

Additional amphetamine analogs identified in the illicit drug market are N-ethylamphetamine,90,91 N,N-dimethylamphetamine92 and 4-methylamphetamine.93-95 Neither the method of manufacture nor the impurities of manufacture have been reported for these analogs; however, N-ethylamphetamine and N,N-dimethylamphetamine would probably be manufactured in a manner similar to methamphetamine except for changing the amine. 4-Methylamphetamine is most likely produced from either 1-(4-methylphenyl)-2-propanone or 4-methylbenzaldehyde (p-tolualdehyde) since both are commercially available. N-Ethylamphetamine was first detected as a drug of abuse by the forensic community during the summer of 1976.90 It was soon found to be clandestinely synthesized in six states and on January 7, 1982, it was placed in Schedule I of the Controlled Substances Act. N,N-Dimethylamphetamine and 4-methylamphetamine have occurred very sporadically in the drug market and neither is regulated under the Controlled Substances Act.

Based on the numerous methods used for the syntheses of either amphetamine or methamphetamine and the presence of either amine as a synthetic contaminant in the other, plus the possibility that either the d or I isomers or racemic mixtures are present, it is useful to reference the pharmacology associated with each of these compounds. Both amphetamine and methamphetamine are used primarily as CNS stimulants. However, they also have anorexic, circulatory (hypertensive) and hyperthermic properties.96,97 Biochemically they are both believed to act by release of biogenic amines, primarily norepinephrine and dopamine, from storage sites in nerve terminals both centrally98 and peripherally. The pharmacological effects of both amines are similar except for the difference in degree of central and peripheral effects.

In animal studies the peripheral pressor activity for racemic amphetamine in dogs is approximately 2�3 times more than racemic methamphetamine99 yet only 0.6 times as active in CNS stimulant activity in mice (ie, racemic methamphetamine is 1.7 times more active).100 In the therapeutic use of racemic amphetamine and methamphetamine in humans, they are used in approximately equal doses with methamphetamine being considered more active as a CNS stimulant.101 The pharmacological effects associated with the enantiomers of the amines are marked. The d isomer of amphetamine is about twice as potent as the racemic form in clinical trials in normal individuals and in patients with narcolepsy, postencephalitic Parkinson's disease and postural hypotension.101 in mice d-amphetamine is 10 times as potent as l-amphetamine in enhancing locomotor activity.102 The peripheral pressor effects in dogs for l-amphetamine and l-methamphetamine is 1.4 times greater than the d isomers.99 Both d- and l-methamphetamine are comparable in peripheral vasoconstrictor activity on the rabbit ear (1:1) and vasopressor response in the cat (1:2). The CNS effects of d-methamphetamine are 4 to 8 times greater than l-methamphetamine depending on the animal model (analeptic, respiratory stimulation and motor activity). l-Methamphetamine is 1/4 to 1/5 times as toxic as d-methamphetamine and l-methamphetamine causes a more rapid death (within 40 minutes) in mice while d-methamphetamine is associated with delayed death (2 hours or more).103 It is readily apparent that the pharmacological/toxicological response to clandestinely prepared amphetamine or methamphetamine can be highly varied depending on the chiral property of the isopropyl amine. Studies related to the optical activity of amphetamine and methamphetamine in the illicit drug market are not currently available although it would be assumed that the racemic mixtures are most prevalent.

The information concerning the pharmacology of the impurities of manufacture are very limited. (+)-N-formyl-1-phenyl-2-aminopropane was reported to have anorectic properties without undesired CNS stimulation or cardiovascular effects.104 The strongly basic amine, 2-(phenylmethyl)phenethylamine has been the most extensively tested. It was initially observed to have local anesthetic activity along with irritant properties.105 In toxicity studies it had a hypotensive effect in rabbits and caused death by respiratory collapse. The 50% lethal dose was 198.5 mg/kg by continuous infusion and 31.7 mg/kg by single dose.106 It has been reported to exhibit strong CNS stimulant activity and to have detrimental effects on isolated rabbit and frog heart muscle. The subcutaneous LD50 in mice was 160 mg/kg;107 the comparable LD50 for racemic amphetamine sulfate is 7 mg/kg.108 Finally, 2-(phenylmethyl)phenethylamine has been implicated in a death in Albuquerque, New Mexico.109 P2P and phenyl-2-propanol exhibit depressant like activity in mice at high doses (loss of righting ability, LRA50, of 215 and 330 mg/kg) and were relatively non-toxic (intraperitoneal LD50 of 520 and 540 mg/kg, respectively).110 There is no literature describing the activity of the remaining impurities of manufacture.

The N-ethylamphetamine, N,N-dimethylamphetamine and 4-methylamphetamine are included in this section because they all exhibit primarily CNS stimulant activity. Based on spontaneous locomotor activity in mice both N-ethyl and N,N-dimethylamphetamine exhibit 1/2 and 1/5 less CNS activity than amphetamine111 Human metabolism studies on these analogs show that 8-15% of N-ethylamphetamine is metabolized to amphetamine112,113 and 15-20% of N,N-dimethylamphetamine is converted to methamphetamine with 0.8-2.4% metabolized to amphetamine.113 These metabolites will contribute significantly to the CNS stimulant activity of these analogs. 4-Methylamphetamine has been explored for clinical use as an anorexigenic agent due to its minimal central stimulant activity and decreased pressor activity relative to amphetamine. Abuse potential for 4-methylamphetamine appears unlikely because it causes overt signs of toxicity (gastric distress, salivation, coughing, vomiting) before causing central stimulation in humans).114

B. Cocaine

Cocaine, the last of the stimulants to be discussed, is obtained from the leaves of plants belonging to the polymorphic species, Erythroxylum coca Lam., from which three varieties are used commercially to produce cocaine. The coca leaves contain three major groupings of alkaloids in which their content varies both qualitatively and quantitatively according to variety and development of leaves. The major alkaloid groups in coca paste are 1) ecgonine derivatives (cocaine, cis- and trans-cinnamoylcocaine, alpha- and beta-truxilline); 2) tropines (tropacocaine, valerine); and 3) hygrines (hygroline, cuscohygrine).115 Cocaine is purified from these additional alkaloids using two different techniques. Pure or pharmaceutical grade cocaine is prepared by initial hydrolysis of the total base extract to obtain l-ecgonine from which cocaine is resynthesized by esterification first with methanol, then with benzoic acid.115 The second method for purification is that reported to be done in the coca-producing areas and involves acid extraction followed by successive recrystallizations.116 This process usually gives an impure cocaine and additional alkaloids observed are benzoylecgonine, methylecgonine, ecgonine, cis- and trans-cinnamoylcocaine and tropacocaine,116-124Fig 8. Methylecgonidine is also observed in illicit cocaine when analyzed using gas chromatography or GC/MS125 and is believed to be an artifact of the analytical procedure (thermal elimination of benzoic acid in the injection port of the gas chromatograph).118 Due to the large quantifies of cocaine coming into the United States, uncut cocaine is often obtained yet contains only 70-90% cocaine as the hydrochloride salt. It was initially anticipated that the combined ecgonine alkaloids could account for the remainder of the samples. The most complete study is by Clark120 of 40 illicit cocaine samples in which all of the ecgonine alkaloids, except benzoylecgonine, were quantitated relative to the cocaine concentration (w/w). Using trimmed means the amount of ecgonine alkaloid relative to cocaine HCl were: trans-cinnamoylcocaine HCl, 0.47% (range 0.1 to 2.61%); cis-cinnamoylcocaine HCl, 0.64% (range 0.1 to 3.18%); ecgonine HCl, 1.33% (range 0.1 to 15.1%, 19 samples were below 0.1% quantitation range and the mean was determined for the remaining 21 samples); methylecgonine HCl, 0.42% (range 0.1 to 2.7%).

Figure 8
Impurities of origin in illicit Cocaine


Due to crystallization behavior similar to cocaine the cinnamoylcocaines are most frequently detected and quantitated in illicit cocaine. In earlier studies the cinnamoylcocaines had been detected in 38%121 to "more than half"116,119 of the samples analyzed, usually in a concentration of 1% or less.116,120,123 Also, small amounts of tropacocaine have infrequently been detected in illicit cocaine.124 Since the ecgonine contaminants do not appear to account for the remainder of the sample in uncut illicit cocaine the volatile components (components which give the distinctive odor to cocaine) have also been studied. Twenty-eight samples were analyzed for acetone and ether (solvents frequently used in recrystallization), methyl benzoate and methycinnamates.126 Acetone was present in all samples analyzed, including the commercial standard, in about 0.5% �0.2%. Diethylether was present in all the samples but at a lower concentration, 0.13% �0.06. Methylbenzoate and methylcinnamates were present in extremely low concentrations, 0.096 �0.098% and 0.024 �0.039%, respectively. It appears that volatile components do not account for the difference. In a single sample of cocaine, benzoylecgonine, methylecgonine and ecgonine were present in concentrations of 2.3, 1.1 and 1.0%, respectively. Cis- and trans-cinnamoylcocaine accounted for 6.9%, water 3%, acetone and ether 0.9% and unknown 1-2%.123 It appears that no major single contaminant accounts for the 10 to 30% of the material in uncut cocaine.

Mention should be made that the total synthesis of cocaine has long been available in the literature;127 its clandestine synthesis has been suggested but has not been routinely observed.4

Cocaine is still used therapeutically due to its combination of effects as a local anesthetic with vasoconstricting activity. Its abuse potential is associated with its CNS-stimulant activity which appears to be associated with its ability to block reuptake of endogenous amines in the sympathetic nervous system as well as to potentiate the effects of exogenous amines.128 The pharmacological effects of the contaminants, benzoylecgonine, methylecgoninne and ecgonine have been studied since all of these alkaloids occur as metabolites of cocaine.129 In rats, no pharmacological effects were observed following intravenous administration of ecgonine (200 mg/kg), methylecgonine (200 mg/kg) or benzoylecgonine (250 mg/kg), whereas intravenous cocaine at 20 mg/kg caused excessively rapid heart beat, convulsions and death within 3-5 minutes. Although benzoylecgonine is inactive following parenteral administration, intracisternal injection (1 mg/kg) to rats produced stimulant effects which were described as being "distinctly different" from those observed with cocaine.130,131 It would appear that ecgonine, methylecgonine or benzoylecgonine present in illicit cocaine would not contribute to the pharmacological effects of cocaine. Surprisingly, no reports describing the pharmacological effects of the cinnamoylcocaines were found, yet both cinnamoylcocaine and cinnamoylecgonine (isomers not specified) have been detected in the urine of cocaine abusers and in a post-mortem bile sample of a cocaine abuser.132

Tropacocaine, the other minor contaminant, has long been recognized as a local anesthetic useful for opthalmic work in humans. Both in rabbits and dogs, tropacocaine exhibits less than one-half the toxicity of cocaine133 and due to the small and infrequent occurrence of tropacocaine, it would be expected to contribute little to the pharmacology associated with illicit cocaine.

IV. Hallucinogens

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A. Phenylalkylamines

The hallucinogenic agents that occur in the illicit drug market can be divided into two categories, the substituted phenylalkylamines and the indole-based compounds.

Figure 9
Synthesis of phenylalkylamine hallucinogens

Table 3

Phenylalkylamine Hallucinogens
Reported in the Illicit Drug Market

The use of the phenylalkylamine hallucinogens has steadily increased since their introduction in the late 60's. Listed in Table III are the phenylalkylamines which have been characterized and identified within the illicit drug market. The general route of synthesis is depicted in Fig 9. The appropriately substituted benzaldehyde is purchased commercially or is prepared clandestinely.3 Using the Knoevenagel reaction the aldehyde is condensed with nitromethane or nitroethane followed by reduction with lithium aluminum hydride or hydrogen and catalyst to give the desired phenylalkylamine. The bromophenylalkylamines are prepared from the appropriate phenylalkylamine by reaction with elemental bromine. An alternative route to the phenylisopropylamines is by preparation of the substituted phenylacetone followed by reductive amination with the appropriate amine (conditions analogous to those used for amphetamine or methamphetamine). This route is known to be used for the clandestine synthesis of 3,4-methylenedioxyamphetamine3 and is the most efficient route to the N-methyl and N-ethyl analogs of 3,4-methylenedioxyamphetamine. Alternative methods used for synthesis of the phenylethylamines, such as mescaline, have been previously reported.2,151 Impurities of manufacture have not been reported for these hallucinogens except for the presence of 4-bromo-2,5-dimethoxyphenethylamine in 4-bromo-2,5-dimethoxyphenylisopropylamine.141 This impurity can be attributed to nitromethane present in the nitroethane in the condensation step. This suggests that depending on the purity of the nitroethane used in the synthesis of the other phenylisopropylamines, related contaminants could be anticipated; they have not been reported.

Due to the numerous phenylalkylamine hallucinogens abused along with those having potential for abuse in the illicit drug market, it is useful to describe the general structure-activity relationships of these compounds as it relates to their hallucinogenic properties. This is facilitated by the excellent reviews that are currently available on hallucinogens.114,152,153 It is unique that extensive quantitative human data on these hallucinogenic phenylalkylamines are known and this can be attributed to the studies by Shulgin and coworkers. Briefly, the incorporation of a methoxyl(s) or methylenedioxy group or combination of these groups into the aromatic ring changes the activity of the phenylisopropylamine from being primarily stimulant to primarily hallucinogenic. The psychotropic potency of the compound depends not only on total density and location of substituents on the aromatic ring but also on the specific nature of the substituent. As is seen in Table III the 2,4,5-trisubstitution pattern gives compounds of optimal hallucinogenic activity. In all of the hallucinogens the 4-substituent is of major importance in that it can increase lipophilicity (increasing CNS penetration), provide resistance to oxidative metabolism and increase hydrophobic binding at the receptor. The nitrogen, two carbons from the aromatic ring, is required for activity and introduction of the methyl group alpha to the nitrogen increases activity over the ethylamine counterpart (this is due to both inhibition of metabolism at the nitrogen and increased lipophilicity). The alpha-methyl also introduces a chiral center in which the (R)-enantiomer is the more active hallucinogen.154 Generally, N-alkylation drastically attenuates the hallucinogenic activity. This is seen with the N-methyl and N-ethyl analogs of 3,4-methylenedioxyamphetamine in which they cause primarily stimulant activity while 3,4-methylenedioxyamphetamine acts primarily as a hallucinogen. Dialkylation, even in 3,4-methylendioxyamphetamine, abolishes hallucinogenic activity. The molecular mechanism responsible for the hallucinogenic effect of these phenylalkylamines is currently unknown. It is important to note that in all of these reviews, hallucinogenic activity is being evaluated and the other peripheral and CNS effects are not the focus of the review. Fatalities have not been reported with hallucinogens except for 4-methoxyamphetamine,135 4-bromo-2,5-dimethoxyamphetamine155 and 3,4-methylenedioxyamphetamine.156 Shulgin considers 4-methoxyamphetamine a "treacherous" drug to study in humans because of its steep dose-response curve. A therapeutic index of about 2.5 is suggested.114 When this drug was first available in the illicit market a number of deaths occurred throughout Canada and the United States. The toxic symptomatology which was very similar to amphetamine included agitation, convulsions, respiratory depression, hypertension and hyperthermia. The molecular mechanism of death is not known. The other hallucinogen associated with a human death, 4-bromo-2,5-dimethoxyamphetamine, appeared to be a relatively safe drug to abuse,114 however, at high doses it was observed to cause disorientation, cardiovascular distress and convulsive complications. The single death associated with this drug was at very low concentrations and based on both toxicological and pathological data it appeared to be due to an acute allergic reaction to the drug rather than its pressor effects.155 3,4-Methylenedioxyamphetamine although relatively non-toxic, at high doses has toxic responses similar to amphetamine toxicity.157,158 For all of the hallucinogens a variety of additional pharmacological effects in animal models are known since these effects were being measured to see if they could be used to accurately predict human activity as a hallucinogen. However, how these pharmacological effects in the animal models could be used to explain toxicological effects in humans has not been evaluated.

B. Indoles

Figure 10
Indole-containing compounds observed in the illicit drug market





























The second category of hallucinogens include the indole-based compounds; the substituted tryptamines and lysergamide alkaloids. The N,N-dialkyltryptamines observed in the illicit drug market (Fig 10) are 3-(2-dimethylaminoethyl)- indole (DMT),2,159 3-(2-diethylaminoethyl)- indole (DET), 3-(2-dipropylaminoethyl)- indole (DPT).161 The tryptamines are usually synthesized by the method of Speeter and Anthony162 (Fig 11) or by the gramine method.163 The related tryptamines, alpha-methyltryptamine164,165 and 5-methoxy-N,N-dimethyltryptamine166 have been identified in the illicit drug market. The characterization of synthetic contaminants has been reported only for 3-(2-pyrrolidinoethyl)indole. It appeared to be synthesized using the Speeter and Anthony method based on the isolation and characterization of 3-indolyl-glyoxypyrrolidide and N-[1-hydroxy-2-(3-indolyl)ethyl]pyrrolidine present in the sample.161 In the same study a comparable intermediate, 1-(N,N-diethylamino)-2-(3-indolyl)ethan-1-ol, was also identified when preparing the N,N-diethyltryptamine by this method. These carbinolamine contaminants are very unusual in that they were reported to be stable to acid-base extraction and preparative TLC purification. It is probable that the carbinolamine intermediates are incorrectly identified and are the more stable N-[2-hydroxy-2-(3-indolyl)ethyljpyrrolidine and 1-(N,N-diethyl)-2-(3-indolyl)ethan-2-ol. The revised structures are consistent with the reported spectral data for both compounds. In addition, 1-(N,N-dimethyl)-2-(3-indolyl)ethan-2-ol has been previously identified as a synthetic contaminant following the reduction of N,N-dimethyl-3-indoleglyoxylamide with lithium aluminum hydride and using a non-acidic workup.167

Figure 11
Synthesis of 3-(2-pyrrolidinoethyl)indole and synthetic impurities observed

* Probable structure of previously identified contaminant

The abuse of these indole derivatives in man is for their hallucinatory effects. The N,N-dialkyltryptamines in which the alkyl group is varied from. methyl to propyl, are all active in humans as hallucinogens at approximately equivalent doses (1 mg/kg by parenteral administration or inhalation).168,169 The duration of hallucinatory effect increases with increasing alkyl substitution on the nitrogen: DMT - one hour, DET - 3 hours, and DPT - 1.5 to 6 hours depending on dose. Based on animal studies the 3-(2-pyrrolidinoaminoethyl)indole is much less behaviorally active than DET and much more toxic.170 5-Methoxy-N,N-dimethyltryptamine is 10 times more potent and alpha-methyltryptamine is two to three times more potent as a hallucinogen in man than the dialkyltrypamines.168 The 3-(2-dimethylamino-1-hydroxyethyl)indole should have decreased hallucinatory activity in humans based on a related series of tryptamines171 and is reported to have hypotensive and diuretic activity.172 It should be emphasized that in addition to the hallucinatory effects of the tryptamines, depending on dose, they exhibit multiple effects on smooth muscle (ie., cardiovascular, uterus, renal, etc.).171

Lysergide (N,N-diethyl-D-lysergamide, LSD) is the most prevalent indole hallucinogen abused, yet clandestine laboratories synthesizing LSD are encountered infrequently? Total synthesis of lysergide by clandestine laboratories has not been reported. Instead the preferred route utilizes lysergic acid obtained through aqueous alkaline cleavage of the ergot alkaloids, ergotamine or ergonovine.2 Activation of the carboxyl group for condensation with diethylamine can then be achieved using a variety of coupling agents.173 There has been a single report of observing N,N-dimethyl-D-lysergamide in the illicit drug market.174 There have been no reports characterizing or quantitating any of the anticipated by-products or impurities in lysergide,175 although they are "present in many seizures."176 This is probably because of the small quantities usually encountered and the variety of dyes that are frequently present in the formulations.

The mechanism by which lysergide causes its hallucinogenic activity is currently unknown.153,177 Lysergide appears to have very strict structural requirements with the dimethyl analog approximately 1/10 the hallucinogenic activity of LSD in humans.178 The intravenous toxicity in rats of the dimethyl analog (LD50 of 0.4 �g/kg) is comparable to lysergide (LD50 of 0.3 �g/kg).177

V. Dissociative Anesthetics - Arylcycloalkylamines

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1-(1-Phenylcyclohexyl)piperidine (phencyclidine, PCP), is the prototypic compound of the class referred to as arylcycloalkylamines.179 Two basic methods of clandestine manufacture of PCP have been observed. The most common method (84% of the clandestine laboratories in the United States), uses 1-piperidinocyclohexanecarbonitrile (PCC) as a synthetic intermediate (Fig 12).3 This intermediate is prepared from the bisulfite addition product of cyclohexanone followed by treatment with potassium cyanide and piperidine180 or by directly mixing piperidine hydrochloride, cyclohexanone and potassium cyanide181 to yield beautiful white, ice-like crystals of PCC. PCC is then dissolved in either diethylether or kerosene and reacted with phenylmagnesium bromide to give PCP. The literature yields for the last step range from 55 to 73%. The alternative method for preparing PCP is through formation of the enamine, 1-(1-cyclohexenyl)piperidine, conversion to the imine with p-toluenesulfonic acid and reaction with phenylmagnesium bromide.182 Approximately 16% of the laboratories were using this method.3 An alternative synthetic intermediate, 1-phenylcyclohexylamine,181 is listed in the Controlled Substances Act as a Schedule II immediate precursor to PCP, however, it has not been observed to be clandestinely manufactured.

Additional arylcycloalkylamines that have been observed are shown in Table IV.182-192 PCC can be used as the synthetic intermediate for the thiophene analog.181 The analogs in which the amine is tertiary are prepared by reaction of the appropriate alpha-aminonitrile with phenylmagnesium bromide. The secondary amines, N-ethyl- and N-propylphenylcyclohexylamine, can be synthesized by acylation of 1-phenylcyclohexylamine followed by reduction with lithium aluminum hydride or by reaction of the imine (formed by the condensation of the amine with cyclohexanone) with phenyllithium. This same reaction of the heterocyclic aminonitriles with phenyllithium does not give the expected arylcycloalkylamine.181

Although it is expected that crystalline PCP would be relatively pure, considerable difficulty is encountered in obtaining it free of PCC even following repeated recrystallizations.193 PCP is frequently obtained coated over green plant material (parsley, mint, marihuana) in which minimal sample purification occurs.194 Indeed, according to one "recipe" following the grignard reaction the reaction mixture is "spooned" directly over the parsley, mixed, the solvent allowed to evaporate then distributed for use.195 The possibility for significant quantities of impurities is quite obvious. It is interesting to note to what extent PCC contamination has been observed. Although abuse of PCP first occurred in the late 60's182 PCC was not detected until early in 1975.196-198 Since then there have been a number of reports in which PCC has been quantitated.194,199-202 An early study suggested that contamination of PCP with PCC was not significant199 while another study suggests extensive contamination.194 Depending on the formulation being analyzed the extent of contamination was highly variable. Generally, tablets and capsules had the lowest level and incidence of contamination while powders and green-plant material usually contained PCC, frequently at very high concentrations. It would be expected that contamination would be even more extensive than that observed. The low levels of PCC can be partially explained by the methods used to analyze for PCC. PCC, as a reactive synthetic intermediate, will partially decompose during thin layer chromatography203 or during the extraction process.194,204 The preparation of the sample prior to analysis is important and unless the analytical procedure is designed to take this decomposition into account, low values for PCC would result. In the one report in which a sensitive colorometric technique was used to quantitate released cyanide from decomposition of PCC, every sample contained PCC, although in low concentrations.202 Piperidine has also been identified as present in PCP but no attempts have been made to quantitate it.205 At least 13 additional nitrogen-containing compounds have been found to be formed during the synthesis of PCP from PCC.181,206 Three of these compounds have been identified as 1-[1-(phenylethyl)cyclohexyl]piperidine (ethyl-PCP), 1-[1-(1,1'-biphenyl-4-yl)cyclohexyl]piperidine (biphenyl-PCP) and 1,1'-1,4-phenylenedicyclohexylidine)-bis[piperidine] (bis-PCP). Respectively, they accounted for 0.5%, 1% and 0.5% of the basic fraction. Analytical methods were developed to assay for these impurities in samples from illicit sources. However, no occurrence or quantitation of these amines in illicit samples was reported.207 Multiple "amine" impurities were reported in illicit 1-(2-thienylcyclohexyl)piperidine, but only piperidine was identified.184 Impurities of manufacture have not been reported for any of the other analogs, although analytical methodology is available for their detection and quantitation.

Table IV

Arylcycloalkylamines Observed in the Illicit Drug
Market and Relative Discriminate Potency in Rats



















The molecular mechanism by which PCP and the related arylcycloalkylamines cause their anesthetic and psychotomimetic effects in man is currently unknown. In contrast to the phenylalkylamine hallucinogens, comparative pharmacology of the arylcycloalkylamines in humans is not available. Their relative activity has been estimated by a multitude of assays on different tissue preparations and animals.208,209 The behavioral activity of these arylalkylamines using rat-discrimination models (Table IV) ranges from 1/10 to 5 times that of PCP. The analogs appear to have pharmacological activity qualitatively similar to PCP.208 This activity seems to parallel what is observed in humans182,183 Most of the analogs illicitly used involve changing piperidine to a different heterocyclic or alkylamine group. The reason for modification at this ring is that the DEA monitors sales of piperidine and in 1976 a one-kilogram bottle of piperidine which was not traceable could command an exorbitantly high price ($1000).182 Currently the sale of piperidine is restricted solely to legitimate and recognized industrial and educational laboratories. In addition to the difficulty in obtaining piperidine, an additional reason for use of the analogs is that the analogs do not show up in many of the routine screens used to monitor drug abusers (radioimmunoassay and thin layer chromatography).186 The presence of the 4-methylpiperidine analog was associated with a theft of three partially filled, 55-gallon drums of piperidine, nine drums of 4-methylpiperidine and six drums of 2-methylpiperidine from a legitimate laboratory in Indiana.210 It appeared as though the 2-methyl- and 4-methylpiperidine may have been mistaken for piperidine during the theft. It further appears that the clandestine chemists recognized that 4-methylpiperidine could be substituted for piperidine in the chemical synthesis, and 1-(1-phenylcyclohexyl)-4-methylpiperidine was soon detected across the country (Washington, D.C., California and New York), ie, waste not want not. The behavioral activity of the arylcycloalkylamines does not always parallel their toxicity. This is seen with 1-(1-phenylcyclohexyl)-4-methylpiperidine which exhibits a much smaller therapeutic index (as observed in mice) than that observed with PCP.189

Many studies have been directed toward determining the pharmacology/toxicology associated with the impurities of manufacture of PCP. The acute toxicity of PCC appears to be associated with its ability to release cyanide. This was initially proposed by Bailey and coworkers198 based on the protective effect of sodium nitrite and sodium thiosulfate on the lethality of PCC in mice. Additional studies have confirmed this interpretation193,201,204 but it appears that the release of cyanide is due to the nascent chemical instability of the molecule and not to metabolic release.211 The recognition that chronic exposure to cyanide can lead to a variety of neurological problems in humans212 and the effects of chronic exposure to sublethal levels of cyanide from PCC could cause comparable problems has been discussed.193 No studies in this area are available due to the absence of a suitable animal model to study chronic cyanide toxicity.213 If PCP contains PCC it would be expected that the toxicity of the mixture would be greatly increased. In animal studies, when PCC is coadministered with PCP, an additive effect was observed for their combined acute toxicity.193 Due to the conflicting reports on the extent of PCC contamination of illicit PCP the actual importance of this contaminant in PCP. is unclear. The toxicity of the alpha-aminonitriles intermediates of the other analogs observed in the illicit drug market, 1-pyrrolidinocyclohexanecarbonitrile and 1-morpholinocyclohexanecarbonitrile, have been evaluated and found to have toxicity at doses equimolar with cyanide.201

When PCC decomposes, in addition to the release of cyanide, there will be formed 1-cyclohexenylpiperidine (when smoked), cyclohexylpiperidinium ion, cyclohexanone and piperidine. In animal studies 1-cyclohexenylpiperidine was relatively nontoxic with an LD50 of 7.72 mmol/kg (dosed orally in corn oil) versus 0.27 mmol/kg for PCP (dosed orally in water).198 The acute toxicity associated with cyclohexanone (LD50 in mice, rats, guinea pigs and rabbits reported to range from 0.93 to 1.54 g/kg)214 and piperidine (therapeutic dosing of piperidine HCl in humans has ranged from 1 to 6 grams/day)215 is of minimal toxicological importance. Although piperidine is of low toxicity it possesses some behavioral activity. It is a normal constituent of the brain, has a nicotine-like action centrally and peripherally, has shown tranquilizing effects on schizophrenic patients and counteracts experimentally induced aggressiveness in mice and rats.216 In mice piperidine can affect motor coordination217 and enhance PCP-induced stimulation in mice,218 although at a relatively high dose. PCP is somewhat unique in that one of the preferred methods of using PCP is by smoking.217,219-221 When PCP is smoked approximately 60% thermally pyrolyzes to 1-phenylcyclohexene220 while only 6% was identified as piperidine.217 The toxicity and behavioral effects of 1-phenylcyclohexene and its metabolites222 were evaluated in mice and they also were considerably less active than PCP in effects on motor coordination. 1-Phenylcyclohexene was less toxic than PCP in mice but exhibited some effect on the mouse immune response depending on dose.223

The remaining contaminants, biphenyl-PCP, ethyl-PCP and bis-PCP were tested in pigeons and quail for behavioral effects. All three amines exhibited different pharmacological effects from PCP. Including PCP, the bis-PCP was the most toxic of the drugs tested (killing pigeons at 20�40 mg/kg and quail at 80 mg/kg). It was proposed that bis-PCP could potentiate and have additive effects on the toxicity of PCP.224

VI. Depressants - Quinazolinones

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Methaqualone is the prototypic quinazolone that is used therapeutically for its sedative and hypnotic effects. Clandestine methaqualone laboratories account for a small percentage of the total number of laboratories seized, however, their occurrence has been increasing since 1978. Recently, the only legitimate manufacturer and supplier of methaqualone in the US has ceased distribution of methaqualone and it is unknown what effect, if any, this will have on the clandestine manufacture of this drug. Methaqualone and analogs which have been observed all contain the quinazolinone nucleus with variation at the 2 and 3 positions. The most frequently encountered synthesis of these compounds (Fig 13) is by N-acylation of anthranilic acid followed by reaction with a substituted aniline under dehydrating conditions (PCl3, POCl3, polyphosphoric acid or simply heating the mixture in a microwave).3 The analogs that have been identified in the illicit drug market are shown in Fig 13.225-232 Mecloqualone although a Schedule I drug in the US, is a legitimately dispensed hypnotic drug in Europe.228

Figure 13
Synthesis of quinazolinones observed in the illicit drug market.

MeMeMethaqualone150-300 mg
MeClMecloqualone150-300 mg




180 mg

Clandestinely prepared methaqualone and analogues are unique in that the drug is primarily sold as tablets rather than powders.226,233 The tablets are frequently well made but are of an off-color (tan, mottled gray) and occasionally have an odor ("sweet" or of acetic anhydride).233-236 Samples of counterfeit methaqualone and mecloqualone are observed to contain unreacted starting materials and processing impurities including anthranilic acid, N-acetylanthranilic acid, ortho-toluidine and ortho-methylacetanilide. There have been no reports on quantitation of these contaminants.

The therapeutic use of methaqualone is as sedative-hyponotic, however, its illicit use appears to be due to its ability to produce a sensual and euphoric state.237 A direct comparison of the pharmacological effects of these compounds in humans has not been reported. Mecloqualone is equipotent with methaqualone in humans but is believed to have a larger therapeutic index based on toxicity studies in mice.238 2-Ethyl-3-phenyl-4-quinazolone at approximately twice the dose of methaqualone had a slightly shorter duration of action in clinical evaluation.239,240 Comparative data for ethaqualone is not available. Of the synthetic byproducts present, only ortho-toluidine is of interest. It has been shown that ortho-toluidine is carcinogenic in mammals (rats, mice),241 and is implicated in a high incidence of bladder cancer and excess mortality in dye workers using it industrially as a chemical intermediate.242 The long term chronic effects of using methaqualone containing varying amounts of ortho-toluidine is unknown but could contribute to a delayed morbidity.

VII. Conclusion

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It is readily apparent from this review that the clandestine pharmaceutical industry has been very effective in providing new drugs and analogs for the illicit drug market. In general, most of these new analogs have been previously reported in the literature with animal data that suggest they would be reasonably active and have similar pharmacological effects to the lead compound in the series. It appears that these compounds do have similar effects and once the user learns to adjust dosage, the drug rarely presents any further significant problems. What is far more surprising is the diversity of pharmacological/toxicological effects that are associated with the impurities in the drug used by the drug abuser. Relatively little is known about the acute or chronic effects of these impurities.

It is hoped that this review will bring attention to some often overlooked variables which can influence the pharmacological effects of clandestinely prepared drugs. First, that these drugs are usually impure and will predictably contain certain synthetic contaminants. Second, that the pharmacological/toxicological properties of the clandestinely manufactured drugs are dependent on the intended active component in addition to the synthetic contaminants. Finally, knowing these contaminants are present will help to better understand the medical consequences following abuse of these drugs.

The author would like to acknowledge the support and assistance Dr. E. L. May has provided during the preparation of this manuscript. The author would also like to recognize the chemists in the Drug Examination Section, Bureau of Forensic Science, Division of Consolidated Laboratory Services, Commonwealth of Virginia, for their assistance in studying the synthetic contaminants observed in drugs in Virginia. Finally, the author is grateful to Dr. R. A. Glennon and Dr. R. B. Westkaemper for their helpful comments and proofreading of this manuscript.

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