Author Topic: Asarone: unraveling of a molecular structure  (Read 2435 times)

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GC_MS

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Asarone: unraveling of a molecular structure
« on: July 16, 2002, 11:13:00 PM »
Asarone is one of those compounds that are much discussed on The Hive. What most bees try to achieve is the synthesis of TMA-2, aka

PiKHAL #158

(http://www.erowid.org/library/books_online/pihkal/pihkal158.shtml). Some pathways have been discribed to synthesize the amphetamine derivative (Rhodium's site describes nitropropene routes from the benzaldehyde and the phenylpropenyl and the Wacker oxidation followed by a good old Leuckart - check out the TMA-2 section of Rhodium's site first if you are completely infamiliar with this compound  ;) ).
Now, some bees might be wondering what a title as "Asarone: unraveling of a molecular structure" has to do with novel synthetic routes... SWIM likes organic chemistry and history, so many bees can find out that SWIM likes to read about the history of organic chemistry  8) . SWIM has some old dirty mothball-stinking books he saved from destruction years ago, at a time he didn't know what amphetamine derivatives were... But that time has passed, and he reads the books again from a very different point. It's that different approach that made him noticing this small pasage in some old German book: the synthesis of asaron to find out its molecular structure. In

Post 332391

(hypo: "piperonal to isosafrole", Novel Discourse)
, I already made a small note about the search for the molecular structure of asaron. Now, I found some more about this "historical search for the true molecular structure".

Meyer und Jacobson, Lehrbuch der organischen Chemie Bd. II Tl. IV, p. 20

(...) In the group ethers from phenoles with unsaturated sidechains, some research projects about the structural elucidation of formerly contradictory structure suggestions , are mentioned. Asarone has been synthesized by Gattermann and Eggers (A) in the following way:



    [ 1 ] - introduction of -CHO by AlCl3-HCN reaction.
    [ 2 ] - Perkin reaction with propionic acid anhydride.

and produced 1-propenyl-2,4,5-trimethoxybenzene.

---

References:

(A) Ber. 32, 289 (1889).

---

This is the text from the book, in Übersetzung from Deutsch  ::) . Now, generally, SWIM sees three things that need to be discussed: precursor, the AlCl3-HCN reaction and the Perkin condensation.

Discussion 1. - Precursor

SWIM checked the availability of the trimethoxybenzene at Merck's ChemDAT, and it appears to be available there as 1,2,4-trimethoxybenzene. The usage of this precursor for the synthesis of TMA-2/4 has been discussed before in

Post 201983

(The_Animal: "1,2,4 Trimethoxybenzene", Chemistry Discourse)
. It should be noted that the same precursor is used for the synthesis of TMA-5 (PiKHAL #161) as well.

Discussion 2. - AlCl3-HCN reaction

This reaction seems similar to the Gattermann Reaction for aldehyde synthesis, which is related to the Hösch Reaction. Methoxy and hydroxy groups have similar mesomeric effects on the phenyl ring, so both are ortho/para directing substituents. When we take a look at the trimethoxybenzene molecule, we note there are  two methoxy groups that "work together": 2,4 will direct substitution towards 3 or 5.



Now, why does the -CHO settle in 5 and not in 3? I have to be honest, SWIM can't give you a straight answer. But there are similar reactions that seem to indicate that the substitution of the -CHO occurs in the para-position of one of the three present methoxy groups. If we check the 1,2,4-trimethoxybenzene again, we see there is only one spot that is in para position of a methoxy and has the added effect of the 2,4 substituents: 5. One of the reactions SWIM uses to support this "theorem" is the synthesis of veratraldehyde from veratrole. This reaction has been set up by... indeed, 

Gattermann!

(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv2p0619) (Organic synthesis refers to Gattermann's article about this synthesis in Ann. 357, 367 (1907)). A small sidenote... SWIM wonders if veratraldehyde can be used to synthesize the 1,2,4 trimethoxybenzene precursor. He'll explain this dream at the end in more depth. Another article that seems to indicate the "validity" of the preference for 5 is an old German patent SWIM found, viz. DE258887 (Verfahren zur Darstellung von Phenolcarbonsäuren). Also not that the Gattermann Reaction displays some similarities with the Reiman-Tiemann Reaction.

Discussion 3. - Perkin

The Perkin Reaction is an aldehyde condensation reaction as explained in

Post 332391

(hypo: "piperonal to isosafrole", Novel Discourse)
. A simple reaction taken from my post there to illustrate the reaction (in this case for anethole from anisaldehyde):

MeO-C6H4-CHO + CH3CH2COONa --> H2O + MeO-C6H4-CH=CMeCOONa

MeO-C6H4-CH=CMeCOOH - CO2 --> MeO-C6H4-CH=CH-CH3


Final notes

1. "And why the f*ck did you gave it that stupid title?" - the synthesis of asarone by Gattermann was part of the proof for the molecular structure of this substance. Since they knew where the double bound would be located using a Perkin condensation reaction, they also knew that asarone was a 1-propenylbenzene and not an allylbenzene derivative.
2. "Dreams" for the synthesis of 1,2,4-trimethoxybenzene from veratraldehyde. Maybe this would be possible: the aldehyde is in para and meta position of the two methoxy groups. It is known that an aromatic -CHO can be transformed to -OH if there is an -OH or -OMe in the ortho or para position (Baeyer-Villiger/Dakin Reaction). I'd like to refer to post

Post 268875

(foxy2: "4-methoxyphenol from p-meobenzaldehyde", Novel Discourse)
for this topic. SWIM thinks the -OMe in the meta position disturbs the formylation of the aromatic aldehyde, but he doesn't know for sure how intensive...  If his proposal would yield 3,4-dimethoxybenzoic acid, then his dream would be completely worthless  ::) .
3. SWIM didn't try the reaction yet. He didn't have the time to do yet, but he had this thing in mind and wanted to share the idea with other interested bees. Comments, positive and negative, always welcome  8) .
4. If some other bee could help me getting reference Ber. 32, 289 (1889), that would be Übercool...

-[ A Friend With W33D Is A Friend Indeed ]-

ChemisTris

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Steric reasons
« Reply #1 on: July 17, 2002, 12:37:00 AM »
"Now, why does the -CHO settle in 5 and not in 3?"
Steric hinderance perhaps, is the governing factor.

i'm determined to make it into the library tomorrow and i'll try to find that ref then.  :)

love the post

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http://www.dhushara.com/book/multinet/democ/wed.htm


tiresias3

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Also..
« Reply #2 on: July 17, 2002, 02:49:00 AM »
Steric influence is certainly a factor, but the bigger issue is that the #5 position is the only available position that is also para to one of the methoxy groups. 

In ortho/para directing electrophilic aromatic substitutions, the para influence has a tendency to win out over the ortho.

I'll look up your question on converting 3,4-dimethoxybenzaldehyde to 1,2,4-trimethoxybenzene.  However, I don't think there will be any problem with the procedure you mention above as long as you methoxylate the phenol afterwards (though I need to double check).

However, if there is an easy procedure for
de-methylene-ating sesamol (3,4-methylenedioxyphenol) and then methoxylating the intermediate (1,2,4-trihydroxybenzene) with dimethyl sulfate or MeI/KOH, that would probably be my first choice synthetic pathway for the formation of 1,2,4-trimethoxybenzene.  Peace.



GC_MS

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-O-CH2-O-
« Reply #3 on: July 17, 2002, 08:12:00 AM »
Breaking the -O-CH2-O- bridge certainly is possible. SWIM thought about using 3,4-methylenedioxyphenol as well, but he can't really tell how easily this compound can be obtained  ::) .
SWIM will look up some reactions to break the methylenedioxy bridge later. One reaction he can clearly remember is the breaking of the bridge with precipitation of C.

-[ A Friend With W33D Is A Friend Indeed ]-

neuromodulator

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Two 1,2,4-trimethoxybenzene synthesis outlines.
« Reply #4 on: July 18, 2002, 12:50:00 AM »
From catechol:

Catechol (1,2-dihydroxybenzene) + 2 eq. MeI/KOH -->  1,2-dimethoxybenzene

1,2-dimethoxybenzene + Br2 + FeBr3 -->  1-bromo-3,4-dimethoxybenzene

1-bromo-3,4-dimethoxybenzene + n-BuLi followed by hydrolysis  -->  3,4-dimethoxyphenol

3,4-dimethoxyphenol + MeI/KOH  -->  1,2,4-trimethoxybenzene.

Notes:
n-BuLi is extremely sensitive to R-OH, where R is an alkyl or an -H, and is thus difficult to use in many cases. 
Also, the bromine substitution will be the only product in the bromination step, and the bromine will add in the 4 position only.

From hydroquinone:

Hydroquinone (1,4-dihydroxybenzene) + 2 eq. MeI/KOH  -->  1,4-dimethoxybenzene

1,4-dimethoxybenzene + Br2 + FeBr3  -->  1-bromo-2,5-dimethoxybenzene

1-bromo-2,5-dimethoxybenzene + n-BuLi followed by hydrolysis  -->  2,5-dimethoxyphenol

2,5-dimethoxyphenol + MeI/KOH  -->  1,2,4-trimethoxybenzene.

Again, 1-bromo-2,5-dimethoxybenzene will be the only major product in that particular step of the above reaction sequence because the bromine is deactivating to the aromatic nucleus once it has been added.



ChemisTris

  • Guest
Ber reference
« Reply #5 on: July 18, 2002, 10:48:00 AM »
I'll post the whole thing, if there is an objection to this, it can be edited.
The "?" refer to parts of the page that were unreadable.



Ber 32 289-291 (1899)

42. L. Gattermann und F. Eggers: Synthese des Asarones.
         (Eingegangen am 2. februar.)

Trotzdem das Asaron mehrfach Gegenstand eingehender chemischer Untersuchungen gewesen ist, kennt man zur Zeit weder die genaue Constitution desselben, noch ist eine Synthese des Körpers ausgeführt worden.

Unsere Kenntnisse bezüglich der Constitution des Asarons lassen sich wie folgt zusammenfassen: Dasselbe leitet sich von dem Trimethyläther des Oxyhydro chinons ab, indem in diesem ein Kernwasserstoffatom durch den Propenylrest ersetzt ist.

An welcher Stelle diese Substitution eingetreten ist und welche Constitution der Propenylgruppe zukommt, ob CH:CH.CH3 oder CH2.CH:CH2, ist nicht entschieden, wenngleich bezüglich des letzteren Punktes die erstere Formel sehr wahrscheinlich gemacht ist. Durch die von dem Einen von uns aufgefundene Sythese aromatischer Aldehyde in dem Stand gesetzt, mit Hülfe von Blausäure die Aldehydgruppe in Phenoläther einführen zu können, haben wir zunächst versucht, ob es viel-leicht zu ermöglichen sei, aus dem Trimethläther des Oxyhydrochinons einen Aldehyd zu erhalten, der möglicher Weise mit dem durch Oxydation aus dem Asaron erhaltenen Asarylaldehyde, welcher die Zusammensetzung eines Trimethoxybenzaldehydes besitzt, identisch sein konnte.

Unsere Versuche in dieser Richtung waren von Erfolg begleitet, indem es uns gelang, in glatter Reaction aus Oxyhydrochinontrimethyläther und Blausäure einen Aldehyd zu erhalten, welcher sich mit dem Asarylaldehyd als identisch erwies. Nunmehr bot auch die Gewinnung des Asarons selbst keine grossen Schwierigkeiten mehr. Führt man unter Anwendung von Proionsäure mit dem Aldehyd die Perkin'sche Zimmtsäuresynthese aus, so erhält man, neben geringeren Mengen der primär entstehenden Zimmtsäure, direct durch Abspaltung von Kohlensäure einen indifferenten Körper, welcher alle Eigenschaften des Asarons zeight.

    Synthese des Asarylaldehydes.
Eine Mischung von 10 g Benzol, 5 g Oxyhydrocinontrimethyläther und 6 ccm Blausäure wird vorsichtig unter Eiskühlung mit 5 g fein gepulvertem Alminiumchlorid versetzt und durch das Reactions-gemisch, welches am Rückflusskühler auf 40-50 [deg] erwärmt wird, vier Stunden lang ein mässiger Strom von trockner, gasförmiger Salzaäure geleitet.
Das dickflüssig gewordene Reactionsproduct wird sodann vorsichtig mit Eiswasser  versetzt, worauf man durch Einleiten von Wasserdampf das Benzol übertreibt. Den nichtflüchtigen Rückstand löst man dann in heissem Wasser auf und kocht mit Thierkohole, worauf nach dem Filtriren der Asarylaldehyd sich beim Erkalten in Form langer, seidenglänzender Nadeln in sehr Ausbeute aus scheidt.

0.1155 g Sbst.: 0.2591 g CO2, 0.0648 g H2O

 (OCH3)3
 /
C6H2  = C10H12O4
 \                       
  CHO
Ber. C 61.22, H 6.12
Gef. 61.18    6.23

Der so erhaltene Aldehyd schmilzt wie der durch Oxydation des Asarons gewonnene Asarylaldehyd bei 114 [deg] und liefert bei der Oxydation mit Permanganat eine Trimthoxybenzoësäure, welche wie die ebenfalls aus dem natürlichen Asaron durch Oxydation erhaltene Asaronsäure bei 144 [deg] schmilzt.

Zur näheren Charakterisirung haben wir das Azin des Asarylaldehydes dargestellt, welches, da es in den üblichen Lösungsmitteln schwer löslich ist, aus Nitrobenzol umkrystallisirt wurde, woraus es in Form derber, gelber Nadeln mit blauem Oberflächenschimmer, die bei 263 [deg] schmelzen, erhalten wird.

   0.109 g Sbst.: 7.2 ccm N (15 [deg], 751 mm).
       C20H24N2O6.  Ber N 7.22.  Gef. N 7.5

Synthese des Asarons.

Eine Mischung von 2 g Asarylaldehyd, 3 g Propionsäureanhydrid und 1 g Natriumpropionat wird in einem Bombenrohr 7 Stunden lang auf 150 [deg] erhitzt. Beim Oeffnen der Bombe zeigte sich starker Druck, von abgespaltener Kohlensäure herrührend. Der Bombeninhalt wurde sodann mit Wasser aufgenommen und der Destillation mit Wasser-dampf unterworfen, wobei das Asaron überdestillirt.
Das alkalisch gemachte Destillat wurde mit Aether aufgenommen, worauf nach dem Verdampfen des letzteren das Asaron in Form eines Oeles zurück-blieb, welches beim Abkühlen jedoch sehr leicht erstarrte. Nachdem es durch Abpressen auf einem Thonteller von geringen Mengen eines sehr intensiv riechenden Oeles befreit war, wurde es in der folgenden   Weise umkrystallisirt: Es wurde in der Kälte in 50-procentigem Alkohol gelöst und die Lösung längere Zeit im Vacuumexsiccator über Schwefelsäure stehen gelassen. Es scheidet sich hierbei das Asaron in Form derber, farbloser Krystalle ab. welche wie das natürliche Product scharf bei 61 [deg] schmelzen. Die Identität beider Körper er-giebt sich fernerhin noch daraus, dass eine Mischung beider wiederum den gleichen Schmelzpunkt zeigte.
0.1091 g Sbst.: 0.2761 g CO2, 0.0748 g H2O.
 
 (OCH3)3
 /
C6H2  = C12H16O3
 \                            
  CH:CH.CH3

Ber. C 69.23, H 7.69
Gef.  69.02,   7.69

Die Ausbeute an Asaron beträgt 60 pCt. der Theorie Das ?
primäre Reactionsproduct der Synthese, die Trimethoxymethylzimmt?-säure, kann aus dem nichtflüchtigen Rückstand der Wasserda ? destillation durch Ausäthern gewonnen werden. Sie krystallisirt aus Alkohol in derben, farblosen Krystallen von Schmp. 157 [deg].

0.1092 g Sbst.: 0.2473 g CO2, 0.0629 g H2O

 (OCH3)3
 /
C6H2  = C13H16O5
 \                            
  CH:C.COOH
     CH3

Ber.  C 61.9,  H 6.35
Gef     61.76     6.40

  Was nun schliesslich die Constitution des Asarylaldehyde bezw. des Asarons anbelengt, so muss ersterem die folgende Formel zukommen:
(the chemical structure of asarone aldehyde with an arrow pointing from the OCH3 to the CHO (para)).

Es ergiebt sich dies aus folgender Ueberlegung: Bei allen bislang ausgeführten Synthesen von Phenolätheraldehyden ist stets die Aldehydgruppe in Parastellung zu dem Oxalkylrest getreten. Ist so tritt keine Synthese ein. Der Analogie nach die folgende Constituttionsformel zu, da bei der eindeutig verlaufenden Zimmtsäuresynthese die Bildung eines anderen Körpers ausgeschlossen ist:
(chemical structure of asarone)
  Heidelberg, Universitätslaboratorium.


:P


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GC_MS

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woohoo
« Reply #6 on: July 18, 2002, 12:49:00 PM »
Thanks alot ChemisTris! Let SWIM archive this so he can do some trials one of the following weeks  ;) .

-[ A Friend With W33D Is A Friend Indeed ]-

neuromodulator

  • Guest
Translation?
« Reply #7 on: July 19, 2002, 01:14:00 AM »
Would anyone care to translate that for the non-German speakers (not necessarily verbatim of course)?

GC_MS

  • Guest
Translating... ?
« Reply #8 on: July 19, 2002, 10:10:00 PM »
Translation... Can't you just learn some German instead  ;) . However, the GoDS blessed you today and some Magical Spirit put a obscure PDF on the net!

Asarone synthesis by Gattermann

(http://www.geocities.com/jolorinus666/file/asarone-ber-32-289-1899.pdf)

Don't ask SWiM who this Spirit was  ;) .

-[ A Friend With W33D Is A Friend Indeed ]-

ChemisTris

  • Guest
Thanks
« Reply #9 on: July 20, 2002, 04:14:00 AM »
Thank you, GC_MS, for the translation  :) .

Got democracy?

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neuromodulator

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On learning the German und so weiter...
« Reply #10 on: July 23, 2002, 11:31:00 PM »
GC_MS,

Well, I suppose I *could* go to graduate school and learn some more German were it not for the financial issue (my parents made me dip into my inheritance just to finally get my B.S.). 

Also, I would of course have to find the right graduate program with the right graduate professor or it would most likely bee a waste of time.  Now, if we could just figure out how to aminate asarone in one easy step....