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#157 TMA
3,4,5-TRIMETHOXYAMPHETAMINE
SYNTHESIS: To a
solution of 39.2 g
3,4,5-trimethoxybenzaldehyde in 30
mL warm
EtOH there was added 15.7 g
nitroethane followed by 1.5 mL
n-
butylamine. The reaction mixture was allowed to stand at 40 °C for
7 days. With cooling and scratching, fine yellow needles were
obtained which, after removal by filtration and air drying, weighed 48
g. Re
crystallization from
EtOH gave
2-nitro-1-(3,4,5-trimethoxyphenyl)propene as yellow
crystals with a mp
of 94-95 °C. Anal. (
C12H15NO5) C,H,N. Alternatively, a
solution of
20 g of the
aldehyde in 75 mL
nitroethane was treated with 4 g
anhydrous ammonium acetate and heated on the steam bath until a deep
red color had been generated. Removal of the excess
solvent/reagent
under vacuum gave a red oil which was
dissolved in an equal volume of
boiling MeOH. On cooling, yellow
crystals of the
nitropropene
separated. Re
crystallization from MeOH gave, after air drying to
constant weight, 13.0 g with the same mp.
Under an inert
atmosphere, 38 g LAH was wetted with 100 mL
anhydrous
Et2O, and then suspended in 1 L dry THF. This was brought up to a
gentle reflux, and there was added, slowly, a
solution of 43.7 g
2-nitro-1-(3,4,5-trimethoxyphenyl)propene in 160 mL THF.
Refluxing
was continued for 36 h, and then the reaction mixture was cooled with
an external ice bath. The excess
hydride was destroyed by the
cautious addition of 38 mL H2O, and this was followed by 38 mL 15%
NaOH, and finally another 114 mL H2O. The inorganic salts which
should have ended up as a loose, granular, easily filterable mass,
looked rather like library paste, but they were filtered nonetheless.
Washing with THF was attempted, but it was not efficient. The
combined filtrate and washes were stripped of
solvent under vacuum
giving 31.5 g of the crude base as an amber oil. This was
dissolved
in 140 mL IPA, neutralized with concentrated HCl (15 mL was required),
and diluted with 650 mL
anhydrous Et2O. There was an initial oily
phase which on continued stirring changed to pale pink solids. These
were finely ground under
CH3CN to give 15.2 g of
3,4,5-trimethoxyamphetamine hydrochloride (TMA) as white
crystals that
melted at 195-211 °C. All
aluminum salts from everywhere were
dissolved in dilute HCl, and 1 Kg of
potassium sodium tartrate was
added. There as added 25%
NaOH allowed the
pH to bring the pH to >9
without the
precipitation of basic alumina. Extraction of this
phase
with
CH2Cl2 was followed by removal of the
solvent and salt formation
as described above, allowed the isolation of an additional 6.4 g TMA.
The product prepared in this manner contains some 10-15%
3,5-dimethoxy-4-hydroxyamphetamine as an impurity. A
solution of 20 g
of the TMA made in this manner in 200 mL 5%
NaOH was extracted with
2x200 mL
CH2Cl2. The pooled extracts were washed with 4x100 mL 5%
NaOH, and the aqueous washes were pooled with the original base
phase.
The organic
phase was stripped of its
CH2Cl2 under vacuum to give an
oil that was
dissolved in 40 mL IPA, neutralized with concentrated
HCl, and diluted with 400 mL
anhydrous Et2O. There was the immediate
formation of spectacular white
crystals of pure
3,4,5-trimethoxyamphetamine hydrochloride, weighing 15.4 g and having
a mp of 220-221 °C. The aqueous
phase was brought to neutrality,
treated with 10 g
potassium di-hydrogen
phosphate, brought to
pH 9.0
with the careful addition of
NaOH, and extracted with 5x100 mL
CH2Cl2.
Evaporation of the
solvent under vacuum gave an oil that spontaneously
crystallized. This product,
3,5-dimethoxy-4-hydroxyamphetamine could
be further purified by
sublimation at 130 °C at 0.2 mm/
Hg. It was a
white
crystalline solid that slowly discolored in the air. The
literature describes a picrate salt with a mp of 225 °C from
EtOH.
DOSAGE: 100 - 250 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 135 mg) I had no nausea, although I
always vomit with mescaline. Somehow my personality was divided and
exposed, and this allowed me to understand my
psychic structure more
clearly. But maybe others could look in there, too. The
psychiatric
use of this drug would be interesting to pursue. It is not completely
pleasant, maybe because of this personal intimacy.
(with 140 mg) There were not the color changes of mescaline there,
but certainly a good humor and an over-appreciation of jokes. The
images behind the eyes were remarkable and tied in with the music, and
I became annoyed at other people's conversations that got in the way.
I was out of it in eight hours. I would equate this to 300 or 350
milligrams of mescaline and I rather think that I would prefer the
latter.
(with 225 mg) There was quite a bit of nausea in the first hour.
Then I found myself becoming emotionally quite
volatile, sometimes
gentle and peaceful, sometimes irritable and pugnacious. It was a day
to be connected in one way or another with music. I was reading
Bernstein's 'Joy of Music' and every phrase was audible to me. On the
radio, Rachmaninoff's 2nd piano concerto on the radio put me in an
eyes-closed foetal position and I was totally involved with the
structure of the music. I was suspended, inverted, held by fine
filigreed strands of the music which had been woven from the arpeggios
and knotted with the chords. The commercials that followed were
irritating, and the next piece, Slaughter on Fifth Avenue, made me
quite violent. I was told that I had a, 'Don't cross me if you know
what is good for you,' look to me. I easily crushed a rose, although
it had been a thing of beauty.
EXTENSIONS AND COMMENTARY: TMA was the very first totally
synthetic
psychedelic
phenethylamine that was found to be active in man, for
which there had been any attempt to describe such drug effects in any
detail. This was the report of research done in
Canada, and it
appeared in 1955, six years before my own report on the material.
There was an earlier report on
TMPEA which is mentioned in the
appropriate recipe, but there were few details given. Also there had
been interest in reports that
adrenalin that had become old and
discolored seemed to elicit central effects in man. The
oxidation
products were identified as the deeply colored
indolic compound
adrenochrome and the colorless
analogue adrenolutin. The controversy
that these reports created just sort of died away, and the
adrenochrome family has never been accepted as being
psychedelic. No
one in the scientific community today is looking in and about the
area, and at present this is considered as an interesting historical
footnote. But, in any case, they are not
phenethylamines and so not
part of this book.
The
Canadian studies with TMA involved the use of a
stroboscope as a
tool for the
induction of visual
phenomena. These experiments used
levels in the 50-150 milligram range, and generally employed
pre-treatment with
Dramamine for the successful prevention of nausea.
There was reported giddiness and light-headedness, and some remarkable
flash-induced visualizations. With higher levels, the visual
syntheses are present without external stimulation. But there is a
thread of negativity that seems to pervade the experience at these
higher levels, and the appearance of a publication that emphasized the
possible antisocial nature to TMA seemed to discourage further medical
exploration. Military interest was maintained however, apparently, as
TMA became a part of the chemical warfare studies where it was
referred to with the code name EA-1319. It had been used in human
trials with
psychiatric patients, but no details of these experiments
have been published.
The presence of a potentially active impurity in TMA deserves some
comment. In the
Canadian work, the material used was described as
melting at 219-220 °C, which is the property given for the
impurity-free material above. If this was the actual material used in
those studies, this impurity (
3,5-dimethoxy-4-hydroxyamphetamine) was
probably not present. The Army studies use a material of unreported
melting point. In my own studies, the lower melting product was used.
There is an intriguing and unanswered question: what contri
bution did
this
phenolic component make to the nature of the observed effects of
TMA? Assays on the isolated contaminant could answer that, but they
have not yet been made.
There is an old saying that has gotten many people into trouble: "If
one is good, then two is better." And if a statement of the measure of
worth of a compound can be made from its potency, then TMA is a step
in the right direction. And this was a chemically simple direction to
follow further. Looking at mescaline as a compound with no
carbons on
its side-chain, and TMA as a mescaline molecule with one
carbon on its
side chain, then what about a compound with two
carbons there, or
three, or nine
carbons?
Using this pattern of naming, TMA can be seen as
alpha-methylmescaline, or AMM. And the two
carbon homologue would be
alpha-ethyl mescaline, or AEM. Its proper name is
2-amino-1-(3,4,5-trimethoxyphenyl)butane. It and its several higher
homologues are discussed in a separate recipe entry called AEM (#1).
A final comment. But maybe a long one! Elsewhere, I have made
comparisons between myristicin and M
MDA, and between
safrole and MDA.
And here there is a similar parallel between elemicin and TMA. What
are these relationships between the essential oils and the
amphetamines? In a word, there are some ten essential oils that have
a three
carbon chain, and each lacks only a molecule of
ammonia to
become an
amphetamine. So, maybe these essential oils, or "almost"
amphetamines, can serve as an index for the corresponding real
amphetamine counterparts. I had originally called this family the
"natural"
amphetamines, but my son suggested calling them the
"essential"
amphetamines, and I like that. At the time that I had
synthesized TMA, back there in the '50s, I had the impulse to explore
this body of Essential Am
phetamines. As the old folk-wisdom says:
"Nature is trying to tell us something."
One of the banes of the archivist is having to choose one pattern of
organization over another. The book store owned by a language scholar
will have the German poets and playwrights and novelists here, and the
French ones over there. Next door, the book store is run by a letters
scholar, and the poetry of the world is here, and the plays of the
world are there, regardless of the language of origin. The same
obtains with spices, and essential oils, and
amphetamines. The spice
cabinet is a rich source of chemical treasures, each source plant
containing a host of com-pounds, some of which are true essential
oils. And the next spice from the next plant has some of the same
components and some new ones. Does one organize by plant (spice or
herb) or by essential oil (
amphetamine)? Let's do it by the ring
substitution pattern of the
amphetamine, and gather the spices and
oils as a secondary collection.
(1) The 4-methoxy pattern. The pivotal essential oil is
4-
allylanisole, or
methyl chavicol, or
estragole (called esdragol in
the old literature). This allyl compound is found in
turpentine,
anise,
fennel, bay, tarragon, and basil. Its smell is light, and
reminiscent of
fennel. The
propenyl analogue is called anethole, or
anise
camphor, and it is found in both anise and camphor. It is a
waxy solid, and has a very intense smell of anise or
fennel. At low
concentrations, it is sweet, as in magnolia blossoms, where it is also
found. The drinks that turn cloudy with water
dilution (Pernod-like
liqueurs, and ouzo and roki), are heavy with it, since it was the
natural flavoring in the original absinthe. That drink was very
popular in the last century, as an intoxicant which produced an
altered state of consciousness beyond that which could be ascribed to
alcohol alone. It contained wormwood, which proved to be
neurologically damaging. The flavorings, such as anethole, are still
big things in
synthetic liqueurs such as vermouth. Old anethole, when
exposed to air and light, gets thick and sticky and yellowish, and
becomes quite disagreeable to taste. Maybe it is polymerizing, or
maybe oxidizing to stuff that dimerizes. Whatever. These changes are
why old spices in the cabinet are best discarded. And adding
ammonia
to any of these natural product oils produces, in principle,
4-methoxyamphetamine,
4-MA.
(2) The
3,4-dimethoxy pattern. The main actor here is
methyleugenol,
or
4-allyl-1,2-dimethoxybenzene. This is located in almost every item
in the spice cabinet. It is in
citronella, bay (which is laurel,
which is myrtle),
pimiento,
allspice, pepper, tree-tea oil, and on and
on. It has a faint smell of cloves, and when dilute is immediately
mistaken for carnations. The
propenyl analogue is, not unreasonably,
methylisoeugenol, a bit more scarce, and seems to always be that
little minor peak in any essential oil analysis. The compounds
missing that
methyl group on the 4-oxygen are famous. The allyl
material is
eugenol, 4-
allylguaiacol, and it is in
cinnamon, nutmeg,
cloves, sassafras and myrrh. You taste it and it burns. You smell it
and think immediately of cloves. And its property as an
anesthetic,
in the form of a clove, is well known in the folk-treatment of
toothaches. Actually, flowers of clove (the gillyflower, like the
carnation) are the small, pointy things that decorate baked hams and,
when stuck into apples, make pomander balls. This
anesthetic property
has recently led to a drug abuse fad, called clove cigarettes. Very
strong, very flavorful, and very
corrosive things from Southeast Asia.
The
eugenol that is present numbs the throat, and allows many strong
cigarettes to be smoked without pain. The
propenyl analogue is
isoeugenol, with a smell that is subtle but very long lasting, used
more in soaps and perfumes than in foods. The
amine addition to the
methyleugenol world produces
3,4-dimethoxyamphetamine, or
3,4-DMA.
The
isomer with the other
methyl group missing is chavibetol
(
3-hydroxy-4-methoxyallylbenzene) and is found in the pepper leaf that
is used with betel nut. A couple of positional rearrangement
isomers
of
methyleugenol are known in the plant world. The
2,4-isomer is
called osmorrhizole, and the conjugated form is isoosmorrhizole or
nothosmyrnol; both are found in carrot-like vegetables. They, with
ammonia, would give
2,4-DMA. And the
3,5-dimethoxyallylbenzene isomer
from artemisia (a pungent herb commonly called mugwort) and from sage,
would give rise to 3,5-DMA. This is an unexplored
isomer which would
be both an antidote for
opium as well as a stimulant, if the classical
reputation of mugwort is transferred to the
amphetamine.
(3) The
3,4-methylenedioxy pattern. One of the most famous essential
oils is
safrole, or
4-allyl-1,2-methylenedioxybenzene. This is the
mainstay of sassafras oil, and it and its conjugated
isomer isosafrole
have a smell that is immediately familiar: root beer! These are among
the most widely distributed essential oils, being present in most of
the spices, including the heavies such as
cinnamon and nutmeg. I am
not aware of the
2,3-isomer ever having been found in nature. Adding
ammonia to either would give
MDA.
(4) The
3-methoxy-4,5-methylenedioxy pattern. The parent compound is
myristicin,
5-allyl-1-methoxy-2,3-methylenedioxybenzene, and the
source of this is nutmeg (or the botanically parallel material, mace).
The nutmeg is the seed of the tree Myristica fragrans and mace is the
fibrous covering of the seed. The two spices are virtually identical
as to their chemical composition. Myristicin and the conjugated
isomer isomyristicin are also found in parsley oil, and in dill. This
was the oil that was actually shown to be converted to M
MDA by the
addition of
ammonia by passage through an in vitro liver preparation.
So here is the major justification for the equation between the
essential oils and the Essential Am
phetamines. Care must be taken to
make an exact distinction between myristicin (this essential oil) and
myristin (the fat) which is really
trimyristin or
glyceryl
trimyristate from nutmeg and coconut. This is the fat from myristic
acid, the C-14 fatty acid, and these two similar names are often
interchanged even in the scientific literature.
(5) The
2-methoxy-3,4-methylenedioxy pattern. This is the second of
the three natural methoxy
methylenedioxy orientations. Croweacin is
2-methoxy-3,4-methylenedioxyallylbenzene, and it takes its name from
the
binomial for the plant
Eriostemon crowei from the worlds of rue
and the citrus plants. It corresponds to the essential
amphetamine
M
MDA-3a. This oil is found in plants of the Family Rutaceae. My
memories of this area of botany are of Ruta graveolens, the common
rue, whose small leaves smelled to me, for all the world, like cat
urine. This plant has always fascinated me because of a most
remarkable recipe that I was given by a very, very conservative
fellow-club member, one evening, after rehearsal. He told me of a
formula that had provided him with the most complete relief from
arthritic pain he had ever known. It was a native decoction he had
learned of many years eariler, when he was traveling in Mexico. One
took equal quantities of three plants, Ruta graveolens (or our common
rue), Rosmarinus officinalis (better known as rosemary), and Cannabis
sativa (which is recognized in many households simply as marijuana).
Three plants all known in folklore, rue as a symbol for repentance,
rosemary as a symbol of remembrance, and pot, well, I guess it is a
symbol of a lot of things to a lot of people. Anyway, equal
quantities of these three plants are allowed to soak in a large
quantity of rubbing
alcohol for a few weeks. Then the
alcoholic
extracts are clarified, and allowed to
evaporate in the open air to a
thick sludge. This then was rubbed on the skin, where the arthritis
was troublesome, and always rubbed in the direction of the extremity.
It was not into, but onto the body that it was applied. All this from
a very conservative Republican friend!
The
methoxy-methylenedioxy pattern is also found in nature with the
2,4,5-orientation pattern. The
allyl-2,4,5-isomer is called
asaricin.
It, and its
propenyl-
isomer, carpacin, are from the
Carpano tree which
grows in the Solomon Islands. All these plants are used in folk
medicine. These two systems, the 2,3,4- and the
2,4,5-orientations,
potentially give rise, with
ammonia, to M
MDA-3a and MMDA-2.
(6) The
3,4,5-trimethoxy pattern. Elemicin is the well studied
essential oil,
5-allyl-1,2,3-trimethoxybenzene, primarily from the oil
of elemi. It is, like myristicin, a component of the Oil of Nutmeg,
but it is also found in several of the Oils of
Camphor, and in the
resin of the Pili in the Philippines. This tree is the source of the
Oil of Elemi. I had found a trace component in nutmeg many years ago
that proved to be 5-
methoxyeugenol, or elemicin without the
4-methyl
group; it is also present in the magnolia plant. The
aldehyde that
corresponds to this is
syringaldehyde, and its prefix has been spun
into many natural products. Any natural product with a syring
somewhere in it has a hydroxy between two methoxys. The
amphetamine
base from elemicin or
isoelemicin would be TMA, the topic of this very
recipe.
(7) The
2,4,5-trimethoxy pattern. There is an essential oil called
asarone that is
2,4,5-trimethoxy-1-propenylbenzene. It is the trans-
or
alpha-isomer, and the cis-isomer is known as beta-asarone. It is
the
isomerization analogue of the much more rare
1-allyl-2,4,5-trimethoxybenzene, gamma-asarone, or euasarone, or
sekishone. Asarone is the major component of Oil of Calamus obtained
from the rhizomes of Acorus calamus, the common Sweet Flag that grows
wild on the edges of swamps throughout North
America,
Europe, and
Asia. It has been used as a flavoring of liqueurs and, as almost
every other plant known to man, has been used as a medicine. In fact,
in Manitoba this plant was called Rat-root by the Cree Indians in the
Lake Winnipeg area known as New
Iceland, and Indian-root by the
Icelandic pioneers. It was used externally for the treatment of
wounds, and internally for most illnesses. There apparently is no
report of central effects. The corresponding
propanone, acoramone (or
2,4,5-trimethoxyphenylacetone), is also present in Oil of Calamus.
The styrene that corresponds to asarone is found in a number of
plants, and is surprisingly toxic to brine shrimp. The older
literature describes an allyl-trimethoxy
benzene called
calamol, but
it has never been pinned down as to structure. The isolation of
gamma-asarone or euasarone from Oil of Xixin (from wild ginger) has
given rise to a potential problem of
nomenclature. One of the Genus
names associated with wild ginger is Asiasarum which looks very much
like the name asarone, which comes from the Genus Acorus. And a
second Genus of medical plants also called wild ginger is simply
called Asarum. There is an Asarum forbesi from central China, and it
is known to give a pleasant smell to the body. And there is Asarum
seiboldi which is largely from Korea and Manchuria. It has many
medical uses, including the treatment of deafness, epilepsy, and
rheumatism. The
amphetamine that would arise from this natural
treasure chest is TMA-2.
(8) The
2,5-dimethoxy-3,4-methylenedioxy pattern. The parent allyl
benzene is apiole (with a final "e") or parsley
camphor, and it is the
major component of parsley seed oil. Its conjugated
isomer is called
isoapiole, and they are valuable as the chemical precurors to the
amination product, DM
MDA. Whereas both of these essential oils are
white solids, there is a green oily liquid that had been broadly used
years ago in medicine, called green, or liquid apiol (without the
final "e"). It comes from the seeds of parsley by
ether extraction,
and when the
chlorophyll has been removed, it is known as yellow
apiol. With the fats removed by
saponification and
distillation, the
old term for the medicine was apiolin. I would assume that any of
these would give rise to white,
crystalline apiole on careful
distillation, but I have never tried to do it. The commercial Oil of
Parsley is so readily available.
(9) The
2,3-dimethoxy-4,5-methylenedioxy pattern. The second of the
three tetraoxygenated essential oils is
1-allyl-2,3-dimethoxy-4,5-methylenedioxybenzene, commonly called
dillapiole and it comes, not surprisingly, from the oils of any of the
several dill plants around the world. It is a thick, almost colorless
liquid, but its
isomerization product,
isodillapiole, is a white
crystalline product which melts sharply. This, by the theoretical
addition of
ammonia, gives DM
MDA-2.
(10) The tetramethoxy pattern. The third and last of the
tetra-oxygenated essential oils, is
1-allyl-2,3,4,5-tetramethoxybenzene. This is present as a minor
component in the oil of parsley, but it is much more easily obtained
by synthesis. It, and its iso-compound, and the
amination product,
are discussed under the last of theTen Essential Am
phetamines, TA.
One must remember that the term "essential" has nothing to do with the
meaning of needed, or required. The word's origin is essence,
something with an odor or smell. Thus, the essential oils are those
oils that have a fragrance, and the Essential Am
phetamines are those
compounds that can, in principle, be made from them by the addition of
ammonia in the body.
There were a few interesting experimental trials that were based on
these natural oils. Methoxy
eugenol was assayed up to a 10 milligram
level, and asarone at up to a 70 milligram level, and neither had any
effects at all. And, in an attempt to challenge the
"
oil-to-amphetamine" concept, I made up a mixture of 1 part
MDA, 2
parts TMA and 5 parts M
MDA. A total of 100 milligrams of this
combination (which I had named the "Pseunut
Cocktail" for
pseudo-nutmeg) should be
equivalent to the
safrole, elemicin and
myristicin that would be in 5 grams of nutmeg. And 100 milligrams
indeed produced quite a sparkle and considerable eye-dilation. But
then, I have never taken 5 grams of nutmeg, so I cannot make any
comparisons.
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