Subject:      Peracetic acid oxidation of isosafrole
From:         rschaap@unixg.ubc.ca (Jessica Robin Schaap)
Date:         1996/04/07

I've searched the ADC archives and haven't found anything on the 
peracetic acid oxidation of isosafrole as a route to MDP-2-P, as this 
would be very attractive to those unable to obtain the 80% formic acid 
that is required for the performic acid oxidation as described by 
Eleusis, Zwitterion, and many journals. Where the performic reaction 
yields the hydroxy formate, the peracetic reaction would yield the 
hydroxy acetate, which not unlike the hydroxy formate could be treated 
with sulfuric acid to form MDP-2-P. Yes? No? Please correct me here if 
I'm wrong as the rest will not matter if I am. Has anyone looked 
into this? As a result, the main reason why I bring this topic to the 
attention of fellow enthusiasts is because I recently came across a paper 
(Daniel Swern, "Epoxidation and Hydroxylation of Ethylenic Compounds with 
Organic Peracids," Organic Reactions) that states that a peracetic acid 
oxidation of isosafrole gives a 100 percent yield, which is further 
accredited to another journal article (Boeseken and Elsen, Rec. trav. 
chim., 48, 363 (1929)). WOW, a 100 percent yield! I'm confused now - does 
the performic acid oxidation of isosafrole to form the hydroxy formate 
also have a 100 percent yield? If so, is it the treatment with sulfuric 
acid where the yield is greatly diminished? I haven't yet obtained the 
original article to which this 100 percent yield is attributed, so if 
anyone interested has access to it I would greatly appreciate a synopsis 
and/or validification of the 100 percent yield (be warned that the 
article is probably written in French as the journal (Rec. trav. chim.) 
is of French origin). Nevertheless, it is obvious that one can form the 
same glycol with a peracetic acid oxidation of isosafrole as with a 
performic acid oxidation, but my main concern is in the actual yield 
of the peracetic acid derived glycol compared to the performic acid 
derived glycol. If anyone has any knowledge as to of any references for 
comparison of these yields, it would be greatly appreciated if you would 
share. Comments and critique would also be greatly appreciated from 
anyone and everyone, but especially the ADC gurus, and you know who you 
are. `-). Thanks in advance!

The Apprentice

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Subject:      Re: Peracetic acid oxidation of isosafrole
From:         eleusis@icubed.net (Eleusis)
Date:         1996/04/11

>**>  is probably written in French as the
>**>  journal (Rec. trav. chim.) is of French 
>**>  origin).

I have missed the original question because my news service through netcom 
is very spotty and currently non-existent from my "new" ISP, but... I 
assume it was asking whether acetic acid could be used instead of formic in 
the infamous peracid oxidation of isosafrole... Correct?

If so, then I would reason that it *can't*. Why? Well, formic acid is a 
helluva lot stronger than acetic.

I could be wrong, thought, and would love it if I was.

A possible *advantage* in using acetic acid, though, would be the lack of 
reducing power. Formic acid is a strong reducing agent as well as an acid, 
and one of the main byproducts in makind MDP-2-P from isosafrole using it 
is the alcohol, MDP-2-Pol - the result of the formic acid cleaving the 
glycol ester and reducing it to the alcohol.

Hence, the highest yield obtainable being somewhere around 63%.

Acetic acid would be less effective in forming the glycol ester, but should 
relatively incapable of reducing said ester to the alcohol. The tradeoff 
could be advantageous, but would require substantial empirical testing to 
determine even suitable reaction conditions.

All in all, a worthy pursuit, though.

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Subject:      Re: Peracetic acid oxidation of isosafrole
From:         f0408002@ccms.ntu.edu.tw (Lee On)
Date:         1996/04/16

: I have missed the original question because my news service through netcom 
: is very spotty and currently non-existent from my "new" ISP, but... I 
: assume it was asking whether acetic acid could be used instead of formic in 
: the infamous peracid oxidation of isosafrole... Correct?

: If so, then I would reason that it *can't*. Why? Well, formic acid is a 
: helluva lot stronger than acetic.

: I could be wrong, thought, and would love it if I was.

: A possible *advantage* in using acetic acid, though, would be the lack of 
: reducing power. Formic acid is a strong reducing agent as well as an acid, 
: and one of the main byproducts in makind MDP-2-P from isosafrole using it 
: is the alcohol, MDP-2-Pol - the result of the formic acid cleaving the 
: glycol ester and reducing it to the alcohol.

: Hence, the highest yield obtainable being somewhere around 63%.

: Acetic acid would be less effective in forming the glycol ester, but should 
: relatively incapable of reducing said ester to the alcohol. The tradeoff 
: could be advantageous, but would require substantial empirical testing to 
: determine even suitable reaction conditions.
 
  I don't think that formic acid will reduce anything in such reaction though
formic acid indeed could be used as reducing agent. The transformation of 
esters to alcohols is also not a reducing reaction.
  The difference between formic and acetic acid is that the former is a 
more strong acid and thus easier to form peracid and make the oxidation 
(epoxydation, dihydroxylation)  reaction faster. The disadvantage in using 
formic acid would be the forming of "explosive" "performic acid".
  The major problem in oxidation of isosafrole using peracid is that the 
100% pure peracid is not easy to get or prepared. 
  In fact, almost pure permaleic acid and perphthalic acid is much more 
stable to handle and prepare. Since maleic acid is more acidic than formic acid
 and acetic acid, the permaleic acid is more reactive than the other two. 
The permaleic acid could be easy prepared from maleic anhydride, urea and 
hydrogen peroxide which are all cheap chemicals. This more stable peracid 
is usually prepared in situ as a solution. The usable solvents are 
usually halogenated solvents, especially halogenated solvents such as 
dichloromethane, chloroform, ethylene dichloride, trichloroethane and 
trichloroethene.   
   The epoxydation product of isosafrole could undergo rearrangemant reaction 
to form methylenedioxyphenylacetone in the presence of Lewis Acid.
   I will try these reaction.

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Subject:      Re: Peracetic acid oxidation of isosafrole
From:         eleusis@icubed.net (Eleusis)
Date:         1996/04/17

> I don't think that formic acid will reduce anything in such
> reaction though formic acid indeed could be used as reducing agent. 

The formic acid is in considerable molar excess to the performic acid, and 
therefore is quite capable of reduction.

> The transformation of esters to alcohols is also not a reducing
> reaction.

Hmmm... Esters are:

  O
  ||  
R-C-O-R

Removal of O and addition of H would not be considered a reduction? 

Seems like a fairly obvious one to me...

Of course, it is a *tricky* one to do, but that is immaterial to the 
discussion ;-).

> The difference between formic and acetic acid is that the former is a
> more strong acid and thus easier to form peracid and make the oxidation
> (epoxydation, dihydroxylation)  reaction faster. The disadvantage in using
> formic acid would be the forming of "explosive" "performic acid".

Not a problem here.. See, the performic (or peracetic) acid is in extremely 
low molar concentration. Therefore, the danger of explosion is nil, and the 
reaction proceeds not through either epoxidation nor glycolation, but 
rather through glycolic alkylation, so to speak. The product is, then, the 
conversion of the double bond to a "glycol ester" (for lack of a better 
term).

The product is saponifiable with alkali metal hydroxide.


> The major problem in oxidation of isosafrole using peracid is that the
> 100% pure peracid is not easy to get or prepared.

Indeed! And yet, one needs only ~1.5 molar peracetic acid in acetic acid to 
do what we want.

> The epoxydation product of isosafrole could undergo rearrangemant
> reaction to form methylenedioxyphenylacetone in the presence of Lewis
> Acid. I will try these reaction.

Correct. *If* you form the epoxide, it could indeed rearrange in the 
presence of, say, Boron Trifluoride-Etherate to form the ketone. 
Unfortunately, I don't think you will have much success forming the epoxide 
with these peracids and if you do, I don't envy you having to then use 
BF3-Etherate to rearrange it.

But I wholeheartedly encourage you to report whatever it is you find.

--------------------------------------------------------------------------

Date: 04-15-96 14:16
From: Eleusis
Subj: TRANSLATION: French Paper on Peracetic Oxidation (long)

I have just completed translating the parts of this interesting 1920's 
paper from Rec. Trav. Chim. which was referenced several days ago in a 
thread started by "The Apprentice".

While the paper's main goal appears to be making soaps, if one skips the 
neutralization step and proceeds to concentration under vacuum and then 
hydrolysis/dehydration with sulfuric acid (as in Shulgin's MDP-2-P from 
Performic Acid process in PiHKAL #109) then you will get MDP-2-P.

The advantage of this method is obvious: it uses acetic acid, available 
from photographic supply stores (glacial only, kids) instead of formic 
acid. Also, it is possible that due to acetic acid's lack of reducing 
power, the yield should be *higher* than with performic.

The disadvantages? I have no empirical data on whether this conjecture is 
substantiated, so it is "buyer beware". Also, it takes a full 48 hours for 
the oxidation step, as compared to 16 with performic. This isn't the one 
to do if you are in a hurry.

I will post the prep for peracetic acid within a day or two... it isn't the 
same as making performic because it is a much weaker acid (requires a 
little catalytic push).

At any rate, here is the text I have translated & transcribed thus far:

Etude Sur L’Oxydation De Quelques Substances Insaturees Par L’Acide 
Perbenzoique et Peracetique.

J. Boeseken et G. Elsen
Translated by Jeffrey Jenkins, my words are enclosed in brackets [].

In a previous communication (1), one of us demonstrated how Peracetic Acid 
oxidation almost always gives a mixture of acetate diols. This reaction 
differentiates itself clearly from oxidation with Perbenzoic Acid almost 
always gives ethylene oxides. The same author then supposed that Peracetic 
Acid could be considered like a “monoacetyl perhydroxy” and that oxidation 
was the result of simple addition of this substance to a double bond (an 
addition with inversion, of [after?] Walden). One could expect that the 
initial product is always a monoacetate [ester?] and that the formation of 
a diacetate or a free diol is respectively due to an ulterior acetylation 
or saponification.

It is also possible that the course of a reaction strongly depends on the 
groups which are directly linked to the unsaturated carbon atoms [the alpha 
carbon, only?]. M. Derx (2), at first, and then M.J. Petrus, Blumberger & 
one of us (3)  had found that the speed of the oxidation by Perbenzoic Acid 
depends on the placement of the double bond in relation to the benzyl core, 
thus Phenyl-1-Propene was attacked much more quickly than Allylbenzene, and 
Phenyl-1-Butene much more so than its isomers, etc...

It appeared to us that the character of the products obtained when using 
Peracetic Acid as an oxidizer would be more or less linked to the speed of 
the oxidation as well. For example, a rapid oxidation would primarily 
produce a double bonded acetate, providing that a slow oxidation would 
cause either the formation of more diacetate or a complication. We have 
oxidized C6H5CH=CHCH2C6H5, Anethol, beta-Isosafrole, and Indene, all with 
the double bond closer to the phenyl side. They are all attacked quickly; 
the first three giving the monoacetates and Indene giving a mixture of 
mono- and di- acetates. In contrast, Allylbenzene gives a diacetate 
probably because the monoacetate is transformed by the long oxidation 
required into the diacetate [a competing reaction].

Safrole gives a complicated mixture: it seems that the molecule was 
partially attacked in another sense.

In the meantime, Eugenol is a derivative of the CH2CH=CH2 bond so it is 
rapidly oxidized giving the monoacetate with a small amount of the 
diacetate.

M.V. Broek (4) found that the tetrabromo derivative of the acid 
d-Eleostearic [?] gives the monoacetate while tetrabromodihydroxystearic 
acid is very slow to react.

These observations indicate that the reaction process begins with a simple 
addition of Peracetic Acid to the double bond. If this addition is very 
slow, the monoacetate of the diol can bond to another part of the molecule 
(safrole), it can be transformed into the diacetate (allylbenzene) or it 
may remain unchanged [ie - unreactive].

It goes without saying that  for the cyclohexene (of which the monoacetate, 
diacetate and free diol were to be obtained), the speed of saponification 
during the isolation process plays an important role [ie - the cyclohexyl 
analogues are more sensitive to the neutralization with .1N KOH than their 
aromatic counterparts].

The Experimental Part

[All ignored except for Isosafrole]

We have chosen this substance because it is an example of cis-trans 
isomerism. However, we have only been able to obtain one of the possible 
isomers of Isosafrole: beta-Isosafrole. the would-be alpha-Isosafrole [a 
benzylenic, C6H5=CHCH3CH3?] isn’t a pure substance, even after troublesome 
fractional separation in an open cathodic device [electrolytic 
separation???] of refraction. The fractions presented such deviations that 
this substance should be a mixture of at least 2 substances with differing 
indices of refraction but of near-identical boiling points. Moreover, 
within this mixture of isomers there should be one which is rapidly 
oxidized [by Peracetic Acid]. This agrees with the results of H.I. Waterman 
& Priester (7) who found that the ordinary transformation of Safrole to 
Isosafrole, when attempting to prepare alpha-Isosafrole, was incomplete and 
actually gave a mixture of beta-Isosafrole and Safrole [assuming that 
alpha-Isosafrole is a benylenic, this makes sense].

[The preparation of beta-isosafrole is omitted - it is merely the 
fractional distillation of crude isosafrole using a Vigreux column.]

16.21g of beta-Isosafrole [C6H5CH=CHCH3] was dissolved in 70mL of 1.52M 
Peracetic Acid (an excess of 6.4% acid, that is to say) and from there 
cooled in an ice bath. The evolution of heat is striking! All of the 
Peracetic Acid was consumed after 2 days; the product of the reaction was 
treated in the manner below [the acetate is saponified using dilute 
potassium hydroxide - this step is not performed if one wishes to make 
MDP-2-P]. The oil thus obtained was a clear-brown in color and had a 
characteristic ethereal odor.

1g of oil required 43.4mL of .1N KOH soln. to saponify.

[The process using alpha-Isosafrole is summarized below working on the 
assumption that alpha-Isosafrole is not the one of interest, but just in 
case...]

16.3g alpha-Isosafrole, having an index of refraction between 1.5668 and 
1.5676 [Sodium D Line, I asssume] was added to 75mL of 14.1M [!!! CAUTION 
!!!], or approximately 5% excess acid [perhaps they meant 1.41M?]. The 
evolution of heat was much less than that of beta-Isosafrole [which would 
agree with a benzylic intermediate]. .45g of the clear-brown oil obtained 
required 18.0mL of .1N KOH soln. to saponify. The presence of a byproduct 
is indicated by the lower amount of alkali needed.

[Other examples deleted as well.]

In summary, we can conclude that the action of Peracetic Acid on an 
unsaturated molecule at the double bond is a simple addition. What happens 
ultimately depends on the character of the formed monoacetate and the 
facility of the starting material towards oxidation. To wit:

1) If the addition proceeds rapidly but acetylation is slow, then the 
monoacetate (either pure or a mixture of isomers) is the product (eg - 
beta-Isosafrole, Diphenylpropene & Eugenol).

2) If both the addition and acetylation proceed rapidly, a considerable 
quantity of the diacetate is formed (eg - Indene and Cyclohexene).

3) If the addition is slow, then the formed monoacetate has enough time to 
react with the starting material forming complex products (eg - 
Allylbenzene).

4) If the addition is slow and the starting material has other sites open 
to attack the reaction gives a complex mixture of products [in my book, a 
“complex mixture of products” usually means “tar”] (eg - Safrole).

Footnotes

1 - Rec. Trav. Chim., v47, pp683-93, 1928
2 - Rec. Trav. Chim., v41, p332, 1922
3 - Rec. Trav. Chim., v44, pp90-5, 1925
4 - Rec. Trav. Chim., v46, p621, 1927
6 - Ber., v42, p3076, 1909
7 - Rec. Trav. Chim., v47, p1027, 1928


--------------------------------------------------------------------------

Subject:      Peracid method confusion
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/07

Pardon my ignorance, but I would like to solicit a clarification of 
the (subst)propenylbenzene + peracid route to (subst)P2P.

If I understand right (and please correct me if I don't),  the general
reaction between an unsaturated compound and a peracid is the
formation of the plain organic acid and an epoxide, with the added
oxygen positioned so as to span the former double bond.  This
epoxide would then generally react in the presence of an organic
acid to form a monoacylated glycol (e.g. the hydroxy formate or
hydroxy acetate), and perhaps to some extent the di-.

Now, in the method Shulgin used in the famous #109, the
substituted propenylbenzene isosafrole is added to performic acid,
the resultant concentrated, then treated with sulfuric acid to get
MDP2P.  Now, what I'm confused about is: what is it that is being 
treated with sulfuric acid?  In "The Compleat ZWITTERION MDMA 
Experience" the commentary seems to indicate that hydrolysis of the 
epoxide was taking place, with a ketone resulting rather than a glycol
due to "the extreme difference in carbocation character on one side
of the epoxide to the other."   In other discussions (e.g. the ZWIT
tragedy doc and Eleusis' doc on improvements to the above
process) the glycol ester is fingered as the culprit.  Eleusis' fine
translation of the french (ptui!) peracetic acid method indicates
the "monoacetate" can be used.  I am somewhat hung up here on
terminology; I took these to refer to the same structure (the
monoacetate=the glycol ester=the monoacylated glycol).  Then I
found in The Apprentice's original post referencing the french
(ptui!) article the statement "it is obvious that one can form the
same glycol with a peracetic acid oxidation of isosafrole as with
a performic acid oxidation."  Now I'm really confused.  Does the term
"glycol" here mean a plain glycol (which would come from hydrolysis
of the epoxide?) or the glycol ester (which shouldn't be the same if
different acids were used, right?).

If it's the epoxide being hydrolysed that is the desired reaction, then
is the reason that the glycol ester is referenced due to a reverse reaction,
i.e. one gets the glycol ester mixed with the organic acid at the end
of the concentration under vacuum, but during hydrolysis with sulfuric
acid one gets back the epoxide which then becomes the ketone?

The reasons that I ask are twofold.  First, I'm confused about how to
employ the product of the peracetic method; can it be used in, or
is it even advantageous for it to be used in Eleusis' improved workup?
Second, the electrolytic method referenced by Fester in his LSD book
(European Patent 0,247,526) results in the same epoxide one would
expect from the peracid addition, but the patent uses lithium iodide to
catalytically transform the epoxide into the phenylacetone.  This
prompts me to wonder if one could just hydrolyse this epoxide with
sulfuric acid or if one would need to react it with an organic acid
(read: cheap acetic) first, and to a lesser extent if lithium iodide
would work on the products of the peracid reactions.  If it works for
the right propenylbenzenes, this electrolytic method seems like a
winner as the chemicals involved can be recycled over and over
again (redundant's in the dictionary twice).  I can post a synopsis
of this method for discussion if anyone wishes me to.

Thanks for any help and my apologies that this was so lengthy.
                                                         --Scrotum:23:1


--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion
From:         hamiltmd@acs.ucalgary.ca (NigNog)
Date:         1996/06/11


> This epoxide would then generally react in the presence of an organic
> acid to form a monoacylated glycol (e.g. the hydroxy formate or
> hydroxy acetate), and perhaps to some extent the di-.
        
        In dilute organic acid you would get the alcohol. Only if you used
concentrated acetic acid or acetic anhydride would you get the acetyl
alcohol.

> Now, what I'm confused about is: what is it that is being 
> treated with sulfuric acid?

        The epoxide.

> Now I'm really confused.  Does the term
> "glycol" here mean a plain glycol (which would come from hydrolysis
> of the epoxide?) or the glycol ester (which shouldn't be the same if
> different acids were used, right?).

        I believe they are refering to the formation of the ester of the
alcohol formed. That would hinder the formation of the ketone.

R-CH=CH2 + RCO3H -> R-CH(OH)-CH3 + RCO2H
R-CH(OH)-CH3 + RCO2H - > R-CH(O2CR)-CH3

        Text structures suck.....
                            
> I can post a synopsis
> of this method for discussion if anyone wishes me to.

        Well I would assume that the epoxide is hydrolysed then oxidised into
the ketone. I think I would have to see the procedure to be of anymore
help.....

        Mike

--------------------------------------------------------------------------

Subject:      Re: Request commentary: safrole vs. isosafrole in forming MDP-2-P
From:         cyberstein@mail.utexas.edu
Date:         1995/09/16

        Actually when you react isosafrole with hydrogen peroxide/formic acid you are
forming performic acid, which reacts with the alkene to form an intermediate epoxide, under 
the acidic conditions of the reaction is decomposed into the 1,2 diol.  This 1,2 diol is 
then reacted with 15% H2SO4 in methanol that dehydrates the diol into the much loved 
(much illegal) 3,4-MDP2P.  I don't know whether or not the KMnO4 reaction would work in 
adequate yield, the only suggestion might be to perform the rxn in anhydrous acetone, with a 
small amount of MgSO4 added to form an insoluble hydroxide precip. aka keeping the solution 
as neutral as possible (so that you don't oxidize the diol, the main problem with this kind 
of hydroxylation).  It has been used with other alkenes to produce diols, but the maximum 
yield I ever saw stated was around 65%, but hell it would be cheap to do. Especially if
you use safrole, which I see no problems with. Something to ponder. 


Cyberstein
"Ideas that make the world round"

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Subject:      Peracid method confusion part 2
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/19

The story of the film so far: Doug and Bob are metropolitan policemen
with a difference...

Sorry.  The story of a neophyte's understanding of the peracid route to
substituted phenylacetones so far, corrections actively solicited...
(thanks out to Mike for responding to my last)

From Deja-news/old organic text combo, (at least)two competing theories:

Theory 1: via epoxide & glycol 
- - - - - - - - - - - - - - - -
Key DjN reference: article <43drhr$rtj@geraldo.cc.utexas.edu> 
(fingers crossed for ASCII structures to turn out right)
The substituted propenylbenzene: R-CH2=CH-CH2
                            O
                            ||
reacts with the peracid: R'-C-O-OH  to form the epoxide: R-CH-CH-CH3
                                                            \ /
                                                             O

which upon acid-catalyzed hydrolysis yields a 1,2-glycol: R-CH-CH-CH3
                                                            |  |
                                                            OH OH
which undergoes a pinacol-pinacolone rearrangement and dehydration due
to the presence of H2SO4 to form the ketone.

Assuming this as the process, the glycol could start to form before the
addition of sulfuric, as the catalyst for this is just H+, so either the
glycol or a combination of the glycol and epoxide would be the result at
the end of concentration under vacuum.  The epoxide produced by the
European patent electrolytic method (see accompanying post) would be
readily dealt with if this theory holds true.

Theory 2: "glycolic alkylation"
- - - - - - - - - - - - - - - - 
Key DjN reference: article <4l3t42$alc_001@icubed.net> (Eleusis)
"the performic (or peracetic) acid is in extremely low molar concentration...
the reaction proceeds not through either epoxidation nor glycolation, but
rather through glycolic alkylation, so to speak.  The product is, then, the
conversion of the double bond to a "glycol ester" (for lack of a better
term)."
                                                   OH OH
                                                   |  |
Um, hmmm... esters are R'-COOR, and glycols are R'-CH-CH-R, so, umm... eh?
A very slightly educated guess:
for our propenylbenzene & performic we get R-CH---CH-CH3
                                             |    |
                                             COOH OH
and with peracetic we get R-CH-----CH-CH3
                            |      |                         ????
                            COOCH3 OH

Well, if this is the case, then to go from the epoxide to the ketone one 
would have to rearrange the epoxide with an electron-deficient catalyst
such as LiI (used in the patent) or perhaps BF3-etherate (as E suggests;
any other ideas?) or figure out how to get either of these "glycol esters"
from the epoxide.  It seems to me you could just do this by reacting the
epoxide with formic or acetic acid, respectively, but then, if I were such
an expert I wouldn't be asking for help, now would I?

I'm dyin' over here.
                                          --Scrotum:23:1

--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion part 2
From:         hamiltmd@acs.ucalgary.ca (NigNog)
Date:         1996/06/21

> Theory 1: via epoxide & glycol

> reacts with the peracid: R'-C-O-OH  to form the epoxide: R-CH-CH-CH3
> which upon acid-catalyzed hydrolysis yields a 1,2-glycol: R-CH-CH-CH3
> which undergoes a pinacol-pinacolone rearrangement and dehydration due
> to the presence of H2SO4 to form the ketone.

        Makes sense so far, my last post was incorrect in that for some reason
I forgot that the glycol was formed, I believe I stated only the
alcohol was formed.

> Assuming this as the process, the glycol could start to form before the
> addition of sulfuric, as the catalyst for this is just H+, so either the
> glycol or a combination of the glycol and epoxide would be the result at
> the end of concentration under vacuum.

        Is water used in the reaction? If ether or some other solvent like
DMSO is used, you wouldn't get diol formation, with H+ would could get
a ring opening reaction, but without a nucleophile, no reaction.

> Theory 2: "glycolic alkylation"

> A very slightly educated guess:
> for our propenylbenzene & performic we get R-CH---CH-CH3
        
        I think the product would be the formate ester of one of the diol
groups, most likely C3, and the ester can serve as a very nice leaving
group in ketone formation.

> Well, if this is the case, then to go from the epoxide to the ketone one
> would have to rearrange the epoxide with an electron-deficient catalyst
> such as LiI (used in the patent) or perhaps BF3-etherate (as E suggests;
> any other ideas?) or figure out how to get either of these "glycol esters"
> from the epoxide.  It seems to me you could just do this by reacting the
> epoxide with formic or acetic acid, respectively, but then, if I were such
> an expert I wouldn't be asking for help, now would I?

        The problem with a pinol type reaction, rearrangements readily occur,
but with only a methyl, phenyl substituted diol, chances are no real
arrangement will incure more stability.

        Concerning the BF3-etherate, Marchs book describes that reaction with
the expoxide, and a methyl shift. As above, shifts aren't likely to
occur.

        Mike

--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion part 2
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/25

>       Is water used in the reaction? If ether or some other solvent like
> DMSO is used, you wouldn't get diol formation, with H+ would could get
> a ring opening reaction, but without a nucleophile, no reaction.

Yep; performic acid is generated in situ from aqueous H2O2 & formic acid,
peracetic beforehand from aq. H2O2, acetic, & H2SO4.  Thus my speculation of
hydrolysis occurring prior to addition of H2SO4.  Sorry if that wasn't too
clear.  Is there some test for epoxides I'm missing?  I'm a bit loathe to
attempt a waterless rxn (obtaining pure peracid, for one) just to satisfy
my curiosity.

>       I think the product would be the formate ester of one of the diol
> groups, most likely C3, and the ester can serve as a very nice leaving
> group in ketone formation.

Click!  My headpiece-device seems to be more greatly illuminated.

>       The problem with a pinol type reaction, rearrangements readily occur,
> but with only a methyl, phenyl substituted diol, chances are no real
> arrangement will incure more stability.

I thought just about anything would be more stable than the epoxide, even the
dimer(?).  Maybe what I should be asking instead of "what else works besides
lith iodide?" would be "what is the particular mechanism occurring in the
patent rearrangement?"

> Concerning the BF3-etherate, Marchs book describes that reaction with the
> expoxide, and a methyl shift. As above, shifts aren't likely to occur.

I'm unfamiliar with this ref; a pointer perhaps?

Vielen Dank.
                                             --Scrotum:23:1

--------------------------------------------------------------------------


Subject:      Re: Peracid method confusion part 2
From:         jabbo@pobox.com (Tim Triche, Jr.)
Date:         1996/06/26

> Yep; performic acid is generated in situ from aqueous H2O2 & formic acid,
> peracetic beforehand from aq. H2O2, acetic, & H2SO4.  Thus my speculation of
> hydrolysis occurring prior to addition of H2SO4.  Sorry if that wasn't too
> clear.  Is there some test for epoxides I'm missing? \

Ummmmmmm, acidic hydrolysis maybe?

> I'm a bit loathe to
> attempt a waterless rxn (obtaining pure peracid, for one) just to satisfy
> my curiosity.

> I thought just about anything would be more stable than the epoxide, even the
> dimer(?).  Maybe what I should be asking instead of "what else works besides
> lith iodide?" would be "what is the particular mechanism occurring in the
> patent rearrangement?"

Gak!  What were youse guys using LiI for, anyways?  I just picked up this
thread and don't feel like going to deja-news.  

> > Concerning the BF3-etherate, Marchs book describes that reaction with the
> > expoxide, and a methyl shift. As above, shifts aren't likely to occur.
> I'm unfamiliar with this ref; a pointer perhaps?

_March's Advanced Organic Chemistry_, Jerry March.  Just got it in the mail.


--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion part 2
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/27

>> clear.  Is there some test for epoxides I'm missing? \
> Ummmmmmm, acidic hydrolysis maybe?

Kinda the pertinent question.

> Gak!  What were youse guys using LiI for, anyways?  I just picked up this
> thread and don't feel like going to deja-news.

Weese guys weren't using LiI (at least not me).  Too hard to get, and nasty, too.
LiI is used in a patent to rearrange the relevant epoxide to
3,4-dimethoxy-phenylacetone (reported to also work for 2,4,5-trimethoxy- and
the ever-popular 3,4-methylenedioxy- ) and I was wondering if another lewis acid
could be substituted.  It is unclear (to me) at this point if the epoxide could
be hydrolysed using H2SO4, chiefly because it is unclear if the epoxide is what
remains after the concentration under vacuum in Shulgin #109 (i.e. in
CA 52,11965(1958)).  This step, obtaining dimethylformamide, and threat of
explosion (not necessarily in that order) seem to be all that stand in the way of
a low-profile, high-yield process for preparing substituted phenylacetones.

                                                  --Scrotum:23:1

--------------------------------------------------------------------------

Subject:      Re:Peracid method confusion part 2
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/19

Summary of the (epoxide-producing) European Patent method for
electrolytically producing phenylacetones from propenylbenzenes:
- - - - - - - - - - -
Like most processes related to this subject, this has already been
hashed over in a.d.c.  See message ID <053319z21081995@anon.penet.fi>
at Deja-news for Dr. X's (harrowing) experience with this reaction.
Keep in mind I don't have the actual patent (0,247,526) and am
relying on the above article and Fester's "Practical LSD Manufacture"
for info.  The patent is for 3,4-dimethoxypropenylbenzene, but Fester
indicates it works for 2,4,5-trimethoxypropenylbenzene (asarone) and
touts it as a general method, while Dr. X indicates it works for isosafrole.

(from Fester, illustrated for asarone)
In a 1 liter beaker, two graphite sheet anodes are placed on either side
of a stainless steel cathode so as to leave a 1cm gap between anode
and cathode.  The cathode has 100cm^2 and the anodes 70cm^2 total
surface area in contact with the soln.  The beaker is filled with either
25g NaBr in 100ml water, 500ml acetonitrile, and 20g asarone, or 27g
NaBr in 200ml water, 400ml dimethylformamide, and 20g asarone.
Magnetic stirring is begun and 3.4 amps put through the system until
24,000 coulombs have gone through (about 117min), keeping the temp
between 10 and 30 C.  Stirring is then stopped.  For the acetonitrile
version, allow the beaker contents to separate and draw off the lower
aqueos phase containing the NaBr, which may be recycled.  The top
phase is stripped of acetonitrile under vacuum with a dry ice trap to
recover acetonitrile for reuse.  The residue is then diluted with 150ml
ethyl acetate.  For the dimethylformamide version, the beaker contents
are diluted with 1 liter of 20% NaCl in water, then extracted with 4x200ml
ethyl acetate.  The combined extracts are stripped under vacuum to a
volume of about 200ml.  The ethyl acetate can be recovered with a
dry-ice trap, and the dimethylformamide is recovered by vacuum
distillation.  The ethyl acetate soln in each case contains the product
epoxide.

The important part: the ethyl acetate/epoxide soln is placed in a flask,
and the flask is flushed w/ nitrogen.  Then 1.5g LiI is added, and the
soln refluxed for 5hr.  The soln is then washed w/ 50ml water to
recover the LiI, and dried over anh. sodium sulfate, then stripped
of ethyl acetate to get the phenylacetone.  Fester claims 20g ketone
yield from either version.

(Dr. X, isosafrole)
Dr. X used a larger setup (100g NaBr, 75ml isosafrole, 2 liters
acetonitrile, 400ml water) and 10 amps for 3.5hr at a temp of 33-36 C.
Dr. X combined several of these large batches and wound up with an
explosion when he/she tried to distill the final residue due to a rapid
polymerization.  Dr. X seemed to feel this was due to the acetonitrile
recycling and not to the size of his/her batch, food for thought.  Dr. X's
yield was "still usable relative to the HCOOH/H202 method" which I
take to be in the neighborhood of 60%, although I would imagine if
half one's crude product BLEW UP the yield would probably SUCK
compared to normal, but what do I know?

Commentary, questions:
Seems one could substitute KBr from the photo supply for NaBr...

Ethyl acetate shouldn't be a problem...

Acetonitrile?  Forget it.  Dimethylformamide?  Maybe... any takers?

Lithium Iodide?  Not likely.  Another catalyst?  BF3-Etherate?  Don't
think so.  Howzabout Magnesium Bromide?  Probably won't work.
Other ideas?

What about hydrolysis a la the performic route?

HOW DOES ONE GO FROM EPOXIDE TO KETONE WHILE AVOIDING
UNWANTED ATTENTION?
        
The $2300 question.
                                                           --Scrotum:23:1

--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion part 2
From:         DrHaney@world.std.com (Daniel R Haney)
Date:         1996/06/24

> Dr. X combined several of these large batches and wound up with an
> explosion when he/she tried to distill the final residue due to a rapid
> polymerization.

  Duh.  Dr. X may have had contaminants like graphite or metals
in there.  Epoxides ain't none too stable by themselves, so 
their handling should be cautious unless the "handlee" wants
to become an object lesson.

  For more info on the chemical properties (no recipes) of
pertinent epoxides, look up anything by Dale Whalen in the last
7 years.

Daniel R. Haney

--------------------------------------------------------------------------

Subject:      Re: Peracid method confusion part 2
From:         nobody@REPLAY.COM (Anonymous)
Date:         1996/06/25

DrHaney@world.std.com (Daniel R Haney) wrote:

>  Duh.  Dr. X may have had contaminants like graphite or metals
> in there.  Epoxides ain't none too stable by themselves, so
> their handling should be cautious unless the "handlee" wants
> to become an object lesson.

The patent's -supposed- to get a pretty good conversion of epoxide
to ketone, and Dr. X (if that is his real name:) had her/its explosion
after this stage, during ketone purification.  Perhaps the rearrangement
is sensitive to impurities, batch size, or is simply overstated in
effectiveness?  It does seem a significant amount of epoxide, or at least
significant amounts of some other unstable rearrangent, remained in Dr.
X's mixture.  How, then to avoid "pulling a Dr. X"?  Besides avoiding
this method like the plague, I mean.

>  For more info on the chemical properties (no recipes) of
> pertinent epoxides, look up anything by Dale Whalen in the last
> 7 years.

Yes, yes.  Very interesting titles, can't wait to hit the library.
Many thanks for the tip.

                                               --Scrotum:23:1
