I am planning on performing a synthesis of 2-phenyl-indole for fun and to make my first hetero-cycle. Org Syn(ref #1) uses ZnCl2 as a lewis acid,
while in the textbook "Operational Organic Chemistry A problem solving approach to the laboratory course(4th ed)" By: John W. Lehman, they use
polyphosphoric acid. I've also read online people have used sulfuric acid, methanesulfonic acid, etc. So it seems like it would be fun to vary the
conditions and test yields, etc. I figure I will start with p-toluene-sulfonic acid as I have quite a bit of excess handy, and compare it to a conc.
sulfuric acid run.
None of these reactions supposedly require inert atmosphere, which I figured was odd, but then again I suppose the indole 2 position isn't all that
incredibly weak to oxidation. Granted it doesn't take much to rip it wide open into kyanuric(spelling) acids, I figure molecular oxygen over the
course of an hour is acceptable. So no gas needed which makes it even more approachable.
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Where I need help is the preparation of the phenylhydrazine. I have Aniline HCl so that's a good starting point. Checking org. syn. thankfully there
is a nice detailed procedure(ref #2).
Though I have a few questions, firstly would sodium metabisulfite work in place of sodium sulfite as the reducing agent of the benzenediazonium
hydrochloride? They are apparently gassing SO2 into a solution of NaOH to make Na2SO3? That could be omitted because, this is simply preparing sodium
sulfite and extra dissolved SO2 gas.
At the bottom of the article(ref #2) they claim an electroreduction has been done to recover quantitative yields rather then this stinky alkaline
sulfite solution stuff. Though the article is nowhere to be found, Takayanagi, J. Chem. Soc. Japan 53, 427 (1932) [C. A. 27, 233 (1933)]. Does anyone
have access to this, is it written in English(probably not)?
edit -
Also found this: McClure, R. E. and A. Lowy (1929). "The electrochemical preparation of phenylhydrazine." Trans. Am. Electrochem. Soc. 56(preprint):
11 pp. Which the same group later published(ref #3) that their use of mercury cathodes lead to phenyl mercuric chloride. So mercury cathodes are out
of the picture. Maybe the japanese paper used lead or something.
In "Practical organic and bio-chemistry", By Robert Henry Aders Plimmer(page 250: http://books.google.com/books?id=7l4gCQoyCM4C&pg=PA250&a...), they use a solution of SnCl2 and HCl to do the reduction. This also seems
significantly less stinky. Though I don't have any tin metal on hand to prepare the SnCl2 I could probably come by it very easily. So that's another
option I guess.
(Thread pertaining to the preparation of SnCl2: http://www.sciencemadness.org/talk/viewthread.php?tid=14174)
Also they mention vaccuum distillation of the final product(phenylhydrazine) I don't think I'm really up for that, could a crystallization suffice to
get it to "pure-enough" for the fischer indole synthesis? They claim that the distillation only removes about 15g to 50g(industrial scale) from about
700g-750g of product, seems like its pretty 'clean' to begin with even on such a huge scale.
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Also any hands on advice on performing these types of reactions would be appreciated. I will be working outside for the phenylhydrazine preparation
because of the HONO(nitrous acid) of course and will be doing both reactions on the millimole scale. Thanks for your time.
#3)THE PREPARATION OF AROMATIC MERCURIC CHLORIDES FROM AROMATIC DIAZONIUM CHLORIDES
Robert E. McClure and Alexander. Lowy
Journal of the American Chemical Society 1931 53 (1), 319-321 http://pubs.acs.org/doi/abs/10.1021/ja01352a047
[Edited on 21-12-2012 by smaerd]kristofvagyok - 21-12-2012 at 13:33
Since I am working with N-heteroaromatic chemistry, I wish a good luck and I would give an advice at the beginning: if you end up with a black tar
(like of the pics down) than don't be surprised and don't give up(:
For your questions: the route from aniline to Ph-hydrazine will work, it's an easy diazotation reaction with an easy reduction, it will also work with
metabisulfite.
For the purification of the Ph-hydrazine is aint that hard. It crystallizes perfectly, it does not need to get vacuum distilled, just a lot extra work
for nothing, it will be pure enough.
For the other references what you have mentioned where they prepared thy Ph-hydrazine with electroreduction and other fancy things.... Forget them.
Diazotation and reduction with SO2 works well, there will be no problem.
For the Fischer type Indole synthesis: NEVER use polyphorphoric acid. I made indole synthesis with that first time ever and eneded up with a brown
tar, similar to soil. Noting was isolateable from that.
Use ZnCl2 as the original recipe mentions or 7-10% cc.H2SO4 in glacial acetic acid as reactant, that worked best for me.smaerd - 21-12-2012 at 14:12
Thanks so much for the advice and encouragement.
I won't use polyphosphoric acid I don't have it anyways. I'll post my successes and hard-ship towards this product in this thread. It seems like a fun
synthetic challenge. Figure I'll make the phenylhydrazine in slight excess to try a couple conditions. The example is pretty academic so there
shouldn't be too many issues but who knows.smaerd - 21-12-2012 at 16:39
Well I scaled down the molar amounts of the reactants and realized to use 10g of aniline I would need to use 95g of sodium metabisulfite, which is a
huge amount(org. syn. uses a 5 molar excess of Na2SO3). I have the amount, but it's going to be fuming off SO2 and it sounds like a really stinky mess
even for the outdoors especially considering it needs to be filtered via vacuum(even more off-gas). Then I'd have to dispose of it as well. I hate
using sulfites for this reason.
I have realized though that stannous chloride is available as a pottery chemical and is pretty affordable for its usefulness. Since it doesn't need to
be anhydrous I could easily digest tin metal in some hot HCl and use as is instead. So I will go this route.
edit: The SnCl2 method also uses 1/3rd the amount of Conc. HCl and uses no dilution, so that's even more appealing for small scale and hobbyist
reasons.
[Edited on 22-12-2012 by smaerd]DJF90 - 23-12-2012 at 16:45
I've done the preparation of 2-iodophenylhydrazine via reduction of the diazonium with SnCl2. The product was isolated as the hydrochloride salt, and
the compound smells quite strongly like capers. Quite nice and unpleasant at the same time. You might decide to scale down further to start with just
one gram. That way if it all goes tits up, the amount invested is minimal and you should have enough material to carry through. You can always scle up
to 10g afterwards once you get a feel for the reaction.smaerd - 23-12-2012 at 18:48
DJF those were my thoughts as well. I was planning ahead to run a few tests in parallel. I would never start a new organic reaction on the 10 gram
scale, because reagents are expensive and I know murphy's law like the back of my hand. Waiting for some B.S. with my debit card to be worked out then
I'll be scooping up some tin(hopefully not contaminated with lead) and documenting the efforts.
Another good reason not too make a "lot" of phenylhydrazine or on an "excess" scale would be oxidation from the atmosphere(Merck Index 12th Edition
page 1256). Not sure if the same goes for the salts as well, but probably. I suppose it could be crashed out of a non-polar solvent via dry acetone or
methanol containing a nice soluble acid such as maleic or tartaric acid to help this; then again I'm not terribly interested in keeping the stuff
around long due to its inherent toxicity. Figure I'll make what I need and use it all on a series of reactions and see which yielded and to what
degree.
Interestingly aq. glycols have been used to facilitate indolization at elevated temperatures(~100*C). I'm curious about running an example of this as
well. I suppose the hydrogen bonding with the leaving ammonia could help push the reaction forward, ultimately though I have only a vague notion of
how this reaction could ensue(mechanistically). We'll see if it works on this substrate(phenylhydrazine and acetophenone).
edit - probably not worthy of a SM publication but I'll do a formal report and hopefully get actual analysis via my university(if my professors are
kind enough to co-operate no promises).
[Edited on 24-12-2012 by smaerd]Magpie - 23-12-2012 at 21:21
Waiting for some B.S. with my debit card to be worked out then I'll be scooping up some tin(hopefully not contaminated with lead) and documenting the
efforts.
A handy source of tin might be Wal-Mart. In my town they sell it as fishing weight (split shot). I have no idea how pure it is, however.zed - 7-1-2013 at 17:49
Never made Phenyl Hydrazine, but I've run the Fischer lots of times. ZnCl2 works nicely.
PPA works OK, but it might be overkill. Like using an elephant gun to shoot a rabbit.
I did end up with brown tar one time, but short-arm distillation at high temperature, under high vacuum.....Cleaned things up nicely. Thereafter,
after just a few short months of trying every known proceedure under the sun, I was able to produce a beautiful crystalline product.
So, perhaps milder conditions than hot PPA might be a wiser choice.smaerd - 8-1-2013 at 05:35
Appreciate all of the advice I have prepared the tin chloride in excess yesterday so that I can begin tinkering today I plan on first trying to use
aq. propylene glycol to facilitate indolization. Figure I will start with the easiest 'cleanest' conditions first then work my way back to more known
catalysts. I'll update my work by editing this post as I go along. About to eat some breakfast and get to cooling some HCl hehehe.
Edit - Update
Synthesis of phenyl hydrazine hydrochloride experimental:
1.40g of Aniline HCl was added to 10mL of conc. HCl, in a 50mL R.B.F. The flask was briefly and gently heated in a heating mantle until all of the
solids dissolved. Then the flask was cool in an ice-bath.
0.75g of NaNO2 was added to 4mL of distilled H2O, this solution was set to sit in an ice-bath. A solution of SnCl2 in HCl prepared the day before was
also cooled in an ice-bath (preparation here: http://www.sciencemadness.org/talk/viewthread.php?tid=14174&...).
30 minutes later it became apparent that the aniline solution had become very viscous. 4mL of distilled H2O was added and the solution allowed to cool
in an attempt to offset this.
The thermometer read 3*C on the aniline solution so the remainder of the reaction began. The nitrite solution was slowly added over the course of 5
minutes. After 2-3 minutes 6.6mL of the SnCl2 HCl solution was quickly added with brief stirring. Instantaneously a white cream precipitate had
formed.
The solution was lightly stirred and allowed to rest for a minute. The solution was vacuum filtered then rinsed with cold conc. HCl solution. The
solid was still moist but it was weighed anyways and came to a mass of 1.90g, this was transferred to a 50mL RBF as is for the indolization attempt.
(failed)Preparation of 2-Phenyl-Indole using Propylene Glycol and water:
Experimental:
15mL of propylene glycol was added to the moist Phenylhydrazine HCl. Followed by 6mL of distilled H2O. The flask was lowered into a boiling water bath
and fitted with a vigreux column.
Drops of acetophenone were added over the course of 15 minutes. The solution began to turn blood red. Total addition of acetophenone was 1.22g.
After addition the reaction was allowed to be heated on the boiling water bath for an hour and 10 minutes. During this time 65mL of distilled water is
chilled in an ice-bath. The reaction flask is poured into the 65mL of water which formed a pink solution and a hazey suspension of a precipitate as
well as oily droplets of suspected unreacted acetophenone ontop.
50mL of distilled water is added. 20mL of saturated NaCl solution as well as a bit of shaved ice in an attempt to coerce the precipitate further. The
solution was left to rest in an ice-bath.
2 hours later: vacuum filtration yeilded a fine dust and a red oil seeped right through. Extracted the solution with 3x 35mL EtOAc. Performing simple
distillation to remove the solvent, this reaction appears to be a failure.
The solution was concentrated down to 10mL. It will be torched tomorrow in a fire-pit. It was a fun first try but this did not work out.
Conclusion: The propylene glycol reacting with the hydrazine hydrochloride may be specifically for cyclic enol ethers and activated phenylhydrazines.
The experimental I read specifically said to use the phenylhydrazine hydrochloride that's the only reason why I tried it this way.
Next attempts will be using a traditional hydrazone formation. Maybe after a traditional hydrazone formation this solvent combination could facilitate
indolization. Was worth a try and could be worth another try.
[Edited on 8-1-2013 by smaerd]zed - 10-1-2013 at 13:51
Phenylhydrazine hydrochloride? Never done it that way. Generally, just Phenylhydrazine and a ketone, in ethanol. Heat it on a water bath to remove
the ethanol and The H2O produced...And Bingo, you have the Phenylhydrazone of your ketone. These are mild conditions.
Treat the Phenylhydrazone with your agent of choice to produce the corresponding Indole.
PPA can be produced nicely at home via microwaving either Mono-ammonium phosphate or Phosphoric Acid, under vacuum. Otherwise, a single kilo
generally costs about a hundred bucks from a major chemical supplier. Pretty spendy for dehydrated phosphoric acid. smaerd - 10-1-2013 at 18:24
I read about it in a paper using different substrates, I thought it was bizarre as well but figured I'd try it out. I'll be doing typical hydrazone
preparation from here on, just need to distill some DCM for pulling the freebase phenylhydrazine. Nice tip on the PPA, I'll keep it in mind.
Figure if I make 2x the phenylhydrazine I can easily do two indolization attempts in a day. Wishing I had another heating mantle controller so I could
run some tests in parallel.
Think I might also try a bismuth trichloride catalyzed reaction just for kicks.
