Notes on isolating myristicin from parsley seed oil and the difficulties of permanganate oxidation of isomyristicin to myristicin aldehyde
I'm hoping this thread will spur some positive dialogue regarding permanganate oxidations of alkenes (isomyristicin in this case) to the corresponding
aldehydes.
In spite of abysmal yields (45% is usually considered a "best case"), permanganate oxidations of alkenes to corresponding aldehydes nevertheless
remain appealing to dilletante chemists in that they require only basic reagents (potassium permanganate, water, and a suitable base) and are
procedurally (deceptively/) simple.
This short file is the confessional of a sad-sack that can't seem to oxidize alkenes into aldehydes to save her life; it is hoped that what follows
will spur some positive dialogue related to permanganate oxidations, which are now widely reviled around the author's sorority house as the messiest,
most inelegant, and lowest-yielding reactions one could reasonably attempt in the field of organic chemistry.
Before we begin, the author would like to share her experience isolating myristicin from parsley seed oil. Until recently, Common Knowledge (tm) had
it that myristicin was generally only obtainable from nutmeg oil, where it was such a tiny constituent (< 10%) of said oil that any attempt to
isolate it with any attention to sizable volume or purity via fractional distillation represented a Herculean task that would inevitably frustrate all
but the most OCD-addled, autistic chemist. Thankfully, thanks for the Internet, it has come to light that there is a perfectly reasonable source of
myristicin in the form of Hungarian parsley seed oil (petroselinum sativum) with myristicin content typically comprising 30 to 40 percent of the
voltaile oil.
The oil obtained by the author had the following main constituents per GCMS analysis;
Principal constituents by %
alpha-pinene 16.8
beta-pinene 12.2
beta-phellandrene 8.9
myristicin 36.6
elemicin 2.3
apiole 15.9
Additionally, there is another strain of parsley seed oil (Petroselinum crispum) that reports an even higher myristicin content (42.75%) in this paper
here.
In either case, the bulk of the superfluous constituents in Hungarian parsley seed oil conveniently have boiling points well below the desired
myristicin fraction, as the list that follows indicates. These can be easily separated by removal via simple distillation, which will leave primarily
myristicin and apiole. Once the lower-boiling constituents are removed, the desired myristicin is then distilled out via careful fractional
distillation. The following boiling points of the primary constituents of Hungarian parsley seed oil are thus noted:
Once myristicin of satisfactory purity is obtained, it was easily converted to isomyristicin by using the standard isomerization procedure: refluxing
myristicin in absolute ethanol with potassium hydroxide for 24 hours and extracting the residue with DCM (the journal article that follows contains a
good writeup here, as does the entry under 'MMDA' in Shulgin's tome Pihkal.) In the writeup that follows, the authors use the crude isomyristicin
obtained without further purification, but the author did not find the crude product to be aesthetically satisfactory, and therefore distilled it to
yield a pleasant-smelling "nutmeggy" light yellow oil.
The preparation of myristicin aldehyde was then attempted per this writeup here:
"Isomyristicin (8 g.) was made into an emulsion with water (500 cc). An aqueous solution of potassium permanganate (22g in 500 cc) was slowly added,
keeping the mixture at 80 degrees C and stirring during the course of an hour and a half. It was kept stirred for another 30 minutes by which time
all the permanganate was reduced. Sufficient 10% aqueous potash was then added in order to make the mixture alkaline and and the manganese dioxide
formed was filtered while hot and washed with hot water. From the filtrate myristic aldehyde crystallized out on cooling. This was filtered off and
the solution extracted twice with ether to remove the aldehyde completely. When the alkaline solution was acidified awith concentrated hydrochloric
acid, myristic acid separated out. It was filtered, washed with a little water and crystallized from methyl alcohol when it come out as big
rectangular prisms with a tendency to taper at the ends and melting at 212-214 C. Yield, 5g."
Note that the author was already no stranger to failing at permanganate oxidations; a previous attempt to prepare 2,4,5 trimethoxybenzaldehyde from
B-asaraone via a similar mechanism had resulted in little more than frustration (a failed reaction is of course bad enough, but the irritatingly large
amount of water-waste byproducts and purple permanganate stains on the glassware just add insult to injury.)During this failed conversion of asarone
to asaronic aldhyde, the author had suspended a mild base (sodium hydrogen carbonate) in the reaction flask during the drip of the permanganate; it
was assumed that this would pre-empt the formation of asaronic acid. HOwever, despite repeated hot-filterings of the precipitated manganese dioxide
out of the reaction mixture and letting the reaction cool, no aldehyde crystallized out in the resulting water; subsequent efforts to extract the
water with methyl-tert butyl ether did not yield any product either.
When attempting to oxidize myristicin to myristicin aldehyde, however, the aforementioned article's procedure was followed verbatim and there was no
caustic/nase present in the reaction flask before the permanganate drip began:
24 g isomyristicin suspended in 500 ml water in a vigorously stirred flask heated in an oil bath with a fairly stable temperature of 90 C. 66 g
potassium permanganate in 750 ml water was added via an addition funnel in over the course of two hours; after the addition of all of the permanganate
the reaction was left stirring for another hour. During the course of the reaction the purple permanganate proceeded to transform itself into black
manganese dioxide.
All permanganate oxidation writeups make a salient point of filtering the solution while hot (presumably to pre-empt any aldehyde crystals from
forming upon cooling and consequently lodging in the filter paper along with the manganese dioxide) but in reality, calling manganaese dioxide
filtration a "sloppy" affair would be putting it mildly. Even pre-moistened double filter papers (diatamaceous earth was no help here either, as it
merely created an insoluble clog) only removed a slim majority of the black mangnaese dioxide and a sizable portion of it still came into the filter
flask; it took several additional filterings (interspersed by periods of re-heating the reaction flask's contents in order to keep it hot) to
facilitate a removal of most of the manganese dioxide, but it seemed all but impossible to filter completely. Injunctions to wash the precipitated
manganese dioxide with hot water simply added more manganese dioxide back into the filter flask. Tired and frustrated, the author let the entire
filtrate cool and it was discovered that the undesired manganese dioxide settled to the bottom. However, there were no crystals of aldehyde upon
cooling as one would expect. 250 ml of 10% KOH was added and then the whole mess was extracted with 2 x 150 ml portions of methyl-tert butyl ether.
The ether extracts were dried, filtered, and removed under vacuum, only to reveal a small amount of what looked like the original starting material
(isomyristicin).
In a desperate move the remaining manganese dioxide filter cakes were added to water which was subsequently basified and extracted with MTBE again,
yielding nothing at all, leaving the author frustrated at bungling what is seemingly such a simple procedure.
If anyone has any luck with these permanganate oxidations please do share; however, it would seem that a much better synthetic approach to myristicin
aldhehyde would involve dispensing the messy permanganate oxidation and methylationg isomyristicin with methylene sulphate as detailed in the previous
article. Better yet, myristicin aldheyde can also be prepared cleanly in high yields from from 5-hydroxyvanillin in a scheme employing DCM and the
phase-transfer catalyst tetrabutylammonium bromide as detailed in ths patent here:
Manganese dioxide might induce further overoxidation of the aldehyde into the corresponding carboxylic acid if the filtration is not done quickly
enough. Also the aldehyde might crystallize and get caught in the small cavities formed by coagulation of manganese dioxide particles. My experience
with KMnO4 oxidations is to swiftly, while hot, remove MnO2 with vacuum filtration using a fritted funnel and some celite. I'm not very pro-drug but
decided to share this anyhow...
[Edited on 30-12-2012 by kavu]killer_lapin - 30-12-2012 at 15:20
Electrochemicaly produced MnO2 can be used according to this paper here. It looks like a simple electrolysis and the anolyte can be recovered and purified to get the aldehyde.S.C. Wack - 30-12-2012 at 17:00
Excerpt from JCS 1204 (1909):
Myristicin (5 parts) was heated for twenty-four hours on the waterbath with a solution of potassium hydroxide (4 parts) in 15 parts of alcohol,
whereby a quantitative yield of isomyristicin was obtained (compare Semmler, Ber., 1891, 24, 3818; Thoms, Ber., 1903, 36, 3446). The latter substance,
in portions of 10 grams at a time, was then shaken into an emulsion with water at 60°, and a solution of 20 grams of potassium permanganate in 500
c.c. of water gradually added with constant agitation, the temperature being kept at 60-65°. After all the permanganate had been added, for which
about an hour was necessary, the mixture was cooled, filtered, and the manganese precipitate well washed with cold water. The precipitate, which
contained the myristicinaldehyde, was dried on a porous plate, and afterwards extracted in a Soxhlet apparatus with chloroform. The chloroform
extracts from several such oxidations were united, the solvent removed, and the solid residue well washed with cold ether to remove unoxidised
isomyristicin. The yield of myristicinaldehyde was 40-45 per cent, of the isomyristicin employed. A quantity of myristicinic acid, varying from 15 to
20 per cent., was always formed by the oxidation, and could be obtained by acidifying the filtrate from the manganese precipitate.
PS "Hungarian" is a bogus descriptor for composition of any plant oil.
[Edited on 31-12-2012 by S.C. Wack]Paddywhacker - 6-1-2013 at 19:48
Sorry, I have no practical experience of this procedure, but I would have ensured that there was never an excess of permanganate by adding it so
slowly that its colour did not persist.
For the work-up, I would suggest dissolving the MnO2 by reduction with bisulfite. You might have to make the mixture acidic, but do so only in the
presence of bisulfite to prevent over-oxidation. The aldehyde will be contaminated with any acid if you crystallise/extract from acid solution, but
you can separate them afterwards.
As an alternative to permanganate have you considered ozonolysis?AndersHoveland - 6-1-2013 at 20:36
For making aldehydes by oxidation, you will need to use selective oxidizing agents, otherwise the yields will be very poor. Aldehydes tend to get
oxidized to carboxylic acids.
Typical selective oxidizers used for obtaining aldehydes are 2-Iodoxybenzoic acid or pyridium chlorochromate. Apparently the adduct of pyridine and
SO3, in the presence of trimethylamine which acts as the base, can also be used to oxidize alcohols to aldehydes, in up to 99% yield (Parikh–Doering
reaction). zed - 7-1-2013 at 16:28
Myristicin Aldehyde.....Hard to come by. I've been wondering what it tastes like.
Would it be a good flavor for icecream?
Shulgin used an interesting proceedure in Phikal. Wherein, he did things ass-backwards, by producing Myristicin Aldehyde from the
Beta-Nitropropenyl-Benzene, via a reverse aldol type reaction.
Take your Myristicin. Nitrate it either via Tetra-Nitromethane, or some other, less hazardous proceedure that is unlikely to kill you. Then, react
the resultant Beta-Nitropropenyl Benzene, with a Benzylamine......Distill off the liberated Nitroethane, and hydrolyse your product to liberate
Myristicin Aldehyde.
(from Oil of Nutmeg) The careful distillation of Oil of Nutmeg (or the Oil of Mace) allowed the isolation of a number of compounds in varying degrees
of purity. The fraction that boiled in the 110-115 °C range at about 1.0 mm/Hg was myristicin (3-methoxy-4,5-methylenedioxyallylbenzene). It
constituted some 7% of the original oil of commerce and, in its original isolated form, was obtained with a purity of 87%. The major contaminant was
elemicin (3,4,5-trimethoxyallylbenzene). A solution of 100 g myristicin in 100 g absolute EtOH was treated with 200 g solid KOH and heated on a steam
bath overnight. Removal of the volatiles under vacuum, flooding the residue with H2O, and extraction with 3x100 mL CH2Cl2 gave, after removal of the
solvent from the combined extracts, a residue of crude isomyristicin (a mixture of the cis- and trans-isomers). This product was distilled, and the
fraction boiling at 125-130 °C at 1 mm/Hg gave 63 g of isomyristicin as a pale yellow oil that spontaneously crystallized. The mp was 41.5-42.5 °C.
Part of the losses associated with the purification of these solids was due to formation of the cis-isomer of isomyristicin, which was an oil.
A solution of 50 g isomyristicin in 300 mL dry acetone containing 24 g pyridine was vigorously stirred and cooled to 0 °C with an ice bath. To this
there was added 54 g tetranitromethane which had been pre-cooled to 0 °C. Stirring was continued for exactly 2 min, and then the reaction was
quenched by the addition of a cold solution of 16.8 g KOH in 300 mL H2O. Stirring was continued until the temperature had again been lowered to near 0
°C. The product was removed by filtration. Extraction of the filtrate with CH2Cl2 and removal of the solvent provided additional nitrostryrene, for a
combined yield of 50.7 g with a mp of 103 °C due to the presence of a small amount of free myristicinaldehyde. A recrystallization from MeOH produced
1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene with a mp of 109-110 °C. This material was completely adequate for the above-described
reduction to MMDA. The conversion of this nitropropene to myristicinaldehyde is an alternative to the lengthy synthesis given above), and can be used
in the preparation of LOPHOPHINE.
A mixture of 50 g 1-(3-methoxy-4,5-methylenedioxyphenyl)-2-nitropropene and 26 g racemic a-methylbenzylamine was heated on the steam bath. The mixture
gradually formed a clear solution with the steady evolution of nitroethane. When the reaction became quiet, there was added a mixture of 20 mL
concentrated HCl in 100 mL H2O. The reaction mixture dissolved completely, and as the temperature continued to rise there was the abrupt
solidification as the formed myristicinaldehyde crystallized out. This product was removed by filtration and, when combined with a second crop
obtained by the hexane extraction of the filtrate, gave 36.9 g of myristicinaldehyde. The mp of 128-129 °C was raised to 133-134 °C by
recrystallization from hexane.
From Pihkal
[Edited on 8-1-2013 by zed]Paddywhacker - 9-1-2013 at 18:08
Myristicin Aldehyde.....Hard to come by. I've been wondering what it tastes like.
Would it be a good flavor for icecream?
...
Interesting question. Also, what does the acid produced as a byproduct smell/taste like - as it's methyl ester, say? D.H., you may not want that
acid, but it could be quite interesting in its own right. At least it will give you something innocuous to show your relatives when they want to see
your lab.
