Microwave-Assited Rapid and Simplified Hydrogenation

Author Topic: Microwave-Assited Rapid and Simplified Hydrogenation

psychokitty

PimpBee posted 10-18-1999 06:16 PM

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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 . . .

WOOOOOW!

(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 . . .

--PK

Xaja

Hive Bee posted 10-18-1999 07:39 PM

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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...

spitball

Pimp Master posted 10-18-1999 08:01 PM

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Fucking awesome. nice find.

-spitball-

KrZ

Hive Bee posted 10-18-1999 08:22 PM

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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.

CHEM GUY

Hive Bee posted 10-18-1999 10:58 PM

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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.

Rhodium

Pimp Master posted 10-19-1999 02:40 PM

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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?

CHEM GUY

Hive Bee posted 10-19-1999 04:49 PM

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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...

psychokitty

PimpBee posted 10-19-1999 06:07 PM

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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.

--PK

--PK

Stonium

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

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CHEMMAN:

quote:

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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.

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

methedrine Synthesis Via HI/Red Phosphorous Reduction of Ephedrine

quote:

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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.

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

[urlhttp://rhodium.lycaeum.org/chemistry/-----hi-redp.txt[/url]

Ta,

Stonium

Stonium

Hive Bee posted 10-19-1999 06:23 PM

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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!

Kiss/Kitty,

Stoni

CHEM GUY

Hive Bee posted 10-19-1999 06:50 PM

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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

CHEM GUY

Hive Bee posted 10-19-1999 07:09 PM

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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

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I can tell you with absolute certainty that

highly acidic conditions + heat induces rearrangement

Slappy

PimpBee posted 10-19-1999 10:09 PM

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Yes, psychokitty was talking about the acetyl ester of Ephedrine.

K.C. Nicolaou
Hive Bee posted 10-20-1999 12:49 AM

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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

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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

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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).

Bye-Bye

psychokitty

PimpBee posted 10-20-1999 02:03 PM

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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.

WOOOOOOW!
--PK

(Lloyd)

Hive Bee posted 10-20-1999 07:35 PM

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Chem Guy why would not the use of the Urushibara catalyst not provide an improvement as regards
safety to this process??

(Lloyd)

psychokitty

PimpBee posted 10-20-1999 08:12 PM

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I take that back. I just did some more research. Phenylhydrazine is indeed VERY toxic and dangerous to
handle.

Oh well.

--PK

CHEM GUY

Hive Bee posted 10-20-1999 09:02 PM

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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."

CHEM GUY

Hive Bee posted 10-20-1999 09:24 PM

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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

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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

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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!!!

CHEM GUY

Hive Bee posted 10-21-1999 12:00 AM

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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...

A SIDE NOTE FOR THE CHEMICALLY INEPT:

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

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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 .

CHEM GUY

Hive Bee posted 10-21-1999 01:17 AM

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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

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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.

dwarfer

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!

dwarfer

Wizard X

PimpBee posted 10-21-1999 08:33 PM

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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

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BTW psychokitty good work. Credit is due on this find.

Xaja

Hive Bee posted 10-21-1999 11:23 PM

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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:

(S)-(+)-alpha-methylphenethylamine.

---- is given as:

(S)-(+)-alpha-N-dimethylphenethylamine.

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

Osmium

PimpBee posted 10-22-1999 03:21 AM

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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.

sunlight

Hive Bee posted 10-22-1999 05:52 AM

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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.

cactus

Hive Bee posted 10-22-1999 03:48 PM

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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

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That's article, not whatever I just wrote

Also...

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).

Osmium

PimpBee posted 10-23-1999 04:10 AM

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I'll try to find it.

CHEM GUY
Hive Bee posted 10-29-1999 06:26 PM

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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,...

Osmium

PimpBee posted 10-30-1999 11:22 AM

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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.

whoops

Hive Bee posted 11-01-1999 01:05 PM

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Nobody would or should there is an easy way

A010

whoops

Hive Bee posted 11-01-1999 01:07 PM

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PK is gona do it????

whoops

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

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c-mon

CHEM GUY

Hive Bee posted 11-02-1999 01:23 PM

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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

dwarfer

Hive Bee posted 01-24-2000 07:39 PM

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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.....

dwarfer
Sploofer

Hive Bee posted 01-27-2000 09:28 PM

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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

View Single Post9922

re: Microwave-Assited Rapid and Simplified Hydrogenation

Sat Sep 10, 2005 11:28 am Reply with quote

Java,

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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java

Consumer

Joined: 07 Feb 2005

Posts: 736

Location: The Mexican Republic

21794.14 Points

View Single Post9933

re: Microwave-Assited Rapid and Simplified Hydrogenation

Sat Sep 10, 2005 8:11 pm Reply with quote

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