A Structural Tour of PiHKALversion 1.1/11-Apr-2000 By rkundalini : rkundalini@hotmail.com, with monkish help.(For information on changes, et cetera, see Changes) 0. Table of Contents
1. Introduction1.1 PiHKAL and This DocumentIn 1991, Alexander (Sasha) and Ann Shulgin published what would have to be the greatest single contribution to pychedelic chemistry, ever. I refer, of course, to PiHKAL, or Phenethylamines I Have Known And Loved. The hefty 978-page tome is actually two books bound together. Book I, presented in three parts, is a fascinating and intimate look into the lives Shura and Alice Borodin, two fictional characters who bear more than a passing resemblance to Sasha and Ann Shulgin. Book II is a compilation of syntheses, "trip reports" and notes regarding 179 substances synthesized, in most cases for the first time, by Sasha Shulgin.Book II was made available online with the permission of the Shuglins, to faciltate the free spread of this information. It is currently available at Erowid and at The Lycaeum, which also has all of the structures online. However, it is worth noting that the Shuglins deserve our support, especially since the U.S. government began persecuting them in 1994. Buy this book if you can spare the cash (US $18.95), preferably from Mind Books, who also deserve our support. With such a large inventory of molecules, the naming scheme is necessarily somewhat esoteric. For the casual reader with no formal chemistry training, such as myself, it is apparent on reading PiKHAL that there is some underlying plan to the collection of substances Shulgin has synthesized, however the specifics of this are quite elusive. For this reason, primarily for my own education, I decided to prepare a kind of "tour" of the substances presented in PiHKAL, outlining the structural relationships and naming schemes. I thought this could be of value to others so I've written it up in the form of this document. For improved readability you may wish to resize the browser until it is just wide enough to lose its horizontal scrollbar.
1.2 Chemistry PrimerAs I noted above, my level of chemistry knowledge is not great, however I hope it is sufficient for the purposes of this tour. For those with no chemsitry knowledge, I present here a quick rundown of what you need to know. Some people people may wish to skip to the bit where the phenethylamine backbone is introduced, or even skip straight to the start of the tour.First of all, all of the materials in PiHKAL are known as compounds. This means that they are made up of innumerable tiny components known as molecules, and that said molecules are all identical and are made up of a number of different atoms. Atoms themselves are made up of a nucleus, which contains protons and neutrons, and the nucleus is surrounded by a cloud of electrons. Phew, talk about reductionism. For the purposes of chemistry, protons, electrons and neutrons can be considered to be indivisible. Electrons and protons are attracted to each-other, which is why the electrons cloud around the nucleus, but they can't get too close or they start being repelled. The esoteric laws of Quantum mechanics end up dictating that there is a series of allowed energies of electrons in atoms, and that only a certain number of electrons can occupy a given level. This number increases with the energy of the level. The normal state of an atom is that all its levels, except perhaps one uppermost layer, are filled, and that the number of electrons is equal to the number of protons in the nucleus. Atoms are given names according to the number of protons : one proton is hydrogen, two protons is helium, three is lithium, etc : these are called the elements. Chemistry, by and large, is about the interactions of atoms, and these interactions usually have something to do with the electrons in the upper-most occupied energy level. This means that in many situations, different elements may behave in similar ways in chemical reactions, if they share the same number of electrons, or same number of free spaces, in their outer shells. The Periodic Table of the Elements provides a graphical representation of this, which we won't go into too deeply here. The most important elements in psychdelic chemistry are carbon, hydrogen and nitrogen. In organic molecules the atoms are joined together with a type of bond known as the covalent bond. In covalent bonding, the atoms more or less share the electrons of their outer shells in order to fill them completely. Since hydrogen has one electron and one free space, two hydrogen atoms can bond to form molecular hydrogen, written as H2 (where the subscript "2" means the molecule has two of these things : this is called an empirical formula). Carbon has four electrons and four empty slots in its outer level, so it can bind to four hydrogen atoms to form CH4, known as methane. Two carbon atoms could also share a pair of electrons, leaving three free slots in each, which we could fill with three hydrogen atoms each in a similar way to what we did with methane, to form C2H6, or ethane. Alternatively, we could share two pairs of electrons, in what is known as a double bond, meaning only two hydrogens are needed for each carbon, to form C2H4, or ethene : the -ene signifies the presence of a double bond. Or, we could connect together three carbon atoms with two single bonds, requiring three hydrogens for each of the two end carbons, and two hydrogens for the middle one: this is C3H6, or propane. If we keep adding atoms of single-bonded carbon and hydrogen, we form butane, pentane, hexane, heptane, octane, and so on. This is called a homologous series. For members of the methane series (the saturated (all single bonds) aliphatic (in chains) hydrocarbons) above propane, one can find several arrangements (called isomers) of each collection of atoms : for example, an isomer of pentane could be made with a central carbon, singly linked to four -CH3 (methyl) groups. This could be called, ambiguously, isopentane, or more precisely, 2,2-dimethylpropane, that is propane with two methyl groups (-CH3s) attached to the 2nd carbon. We could go on forever making ever more complex organic molecules: this is the beauty of carbon. Organic chemistry is like playing with Lego. However, these simple hydrocarbons don't make good drugs, unless you want brain damage, so let's move on. The next thing you need to know about is the benzene ring. Take a CH and singly bond its carbon to the carbon of another CH. Then doubly bond this carbon to the carbon of another CH. Then singly bond that carbon to another CH, doubly bond that carbon to the carbon of another CH, singly bond that carbon to the carbon of another CH, and doubly bond that carbon to the carbon of the original CH. That was a mouthful, from now on we will simply draw the molecules, like this:
Here, each line represents a covalent bond, and each vertex represents a carbon atom. To keep things simple, hydrogen atoms are often left out of pictures of structures, since it is easy to work out where they must go. In this case we know that carbon always wants four bonds, so here each carbon must have one hydrogen hanging off it. Now, it actually turns out that the benzene ring is so small that all of the electrons in the depicted single and double bonds are in fact shared equally among the carbons, so the benzene ring is often drawn like this:
Now, remember before when named a pentane isomer by viewing it as propane with two methyl groups attached? This kind of thing happens quite a bit in organic chemistry, where we can replace one chunk of molecule (in this case a -H) with another (in this case -CH3) that has the same bonding requirements. The chunks are called functional groups, and are often referred to as simply "R", when "R" could be any of several function groups leading to a variety of different molecules based on a common backbone. As you may have surmised, functional groups have names which are often derived from molecules that consist of the functional group plus one or more hydrogens. Hence, -CH3 is refered to as methyl (often shortened to Me). We could also make use of ethyl (-C2H5, Et), propyl, and so-on. Or, we could put an oxygen (which wants to have two bonds) between the group and whatever it is to be tacked on to, to have hydroxy (-OH), methoxy (-OCH3 or MeO), ethoxy, and so-on. Or we could pull the same trick with a sulfur atom to make methylthio (-MeS), ethylthio (-EtS) and so-on. One very imporant functional group is the amine (NH2) group. This is based on ammonia, (NH3), and is a feature of the vast majority of psychoactive substances. If we were to take a benzene ring, use it as a functional group (called phenyl) to tack on to an ethyl group, and tack on an amine on the other end of the ethyl, we would have beta-phenethylamine, like so:
This molecule is the basis of all of the substances described in book
II of PiHKAL. In order to talk about modifications to the molecule, it
is useful to have a way of referring to each carbon atom. Starting
with the benzene ring at the site of the bond to the ethyl, we number
this "1", and travelling in either direction, number the rest 2, 3, 4,
5, 6. Note that one could just as easily have looked at the structure
from the other side (imagine yourself inside the computer monitor or
behind the page) : this is why the 2-position could also be called the
6-position, as long as what was the 3-position was referred to as the
5-position. The other two carbons are called
Phenethylamine itself is not active
Adding or removing an alpha-methyl is a commonly used tactic in structural explorations. Shulgin refers to the alpha-methylated molecule as the three-carbon or 3C- version (or the "amphetamine analogue"), and naturally, when the alpha-methyl is not present, the substance is the two-carbon, 2C- or "phenethylamine analogue". Amphetamine is an interesting substance however it is not a psychedelic. Another substance worth knowing about is dopamine, since it is a neurotransmitter that is intimately involved (along with serotonin, a tryptamine) in the action of the phenethylamines, among many other drugs. Dopamine is 3,4-dihydroxyphenthylamine (the di- means two hydroxys):
Two related endogenous phenethylamines are epinephrine (beta-hydroxy-N-methyldopamine) and norepinephrine (beta-hydroxydopamine), also known as adrenaline and noradrenaline. The difference between these substances is the N-methyl group, and this structural relationship serves as the model for a number of structural variations of other substances as we will see below. Shulgin employed a wide range of functional groups in his creations and it isn't worth bogging ourselves down with the structure of each here: you already have the most common ones. You might refer to an organic chemistry textbook, or perhaps you could even find something at Web-ster's Organic Chemistry Site, if you are interested.
2. Tour of the PhenethylaminesWhat follows is a tour of the substances described in PiHKAL. When discussing variations to structures, it will be convenient to talk as if we are able to just add groups, atoms, even neutrons wherever we like. Of course in real life this is not the case and a small change in structure will sometimes demand an entirely different synthesis strategy.2.1 Substances Derived from MescalineLet's start with the grand-daddy of them all, mescaline:
Mescaline is 3,4,5-trimethoxyphenethylamine, and is of course a beautiful psychedelic found, among other things, in peyote (Lophophora williamsii) and a number of species of columnar cacti of the genus Trichocereus. Let's have a tinker. 2.1.1 The TMAsThe most obvious thing to try is to methylate that alpha carbon, turning the phenethylamine bit into amphetamine. The result in this case is 3,4,5-trimethoxyamphetamine, or simply TMA. One could also move those methoxys around to different positions (there are six possibilities), forming both the phenethylamine (PEA) and amphetamine (A) versions. The following table summarizes these substances:
The PEA versions of TMA-4, TMA-5 and TMA-6 have been made but haven't been tasted : see the corresponding TMA-x entries of PiHKAL. Shulgin also describes three dimethoxylated TMA analogues: 2,4-DMA, 2,5-DMA, 3,4-DMA, and the beta-hydroxylated version of 3,4-DMA, DME (so named due to its alternative full name, 3,4-dimethoxyphenyl-beta-ethanolamine, which is grasping at straws if you ask me). The 2C- version of 3,4-DMA also has an entry: DMPEA, as does its 4-ethoxy homologue, MEPEA, and the N-methylated version of 2,5-DMA, METHYL-DMA. One singly methoxylated analogue and its N-methylated version is included: 4-MA and METHYL-MA. Another TMA-related substance in PiHKAL is TA, which is essentially the superposition of TMA and TMA-2. The rationale for the naming of this substance eludes me. It is the tenth of Shulgin's Ten Essential Amphetamines (see the entry for TMA), so perhaps TA stands for Tenth Amphetamine??
2.1.2 The 4-Substituted MescalinesAs will be seen later, the 4-position seems to be an important factor in determining the nature and potency of effects of phenethylamines. Quite a number of 4-substituted mescalines are described in PiHKAL. The following table lists them according to the 4-substituent:
Starting from the top of the table we have, of course, mescaline. This is followed by 4-D, in which the three hydrogen atoms of the 4-methoxy group are present as the single neutron isotope, deuterium. Next is DESOXY, so-named since it is mescaline with the oxygen removed from the 4-methoxy. This is followed by a series of increasingly massive hydrocarbon substituents, a number of which also have alkylthio versions included at the end of the table. The 3,4-dimethoxy-5-alkoxy versions of E and P are also included in PiHKAL, as ME and MP -- the "M" stands for "meta". Shulgin notes in the entry for PE, and it is worth repeating here, that 3C-BZ (and its untasted phenethylamine version, BZ) has nothing to do with the agent of chemical warfare also known as BZ (thankfully).
2.1.3 The EscalinesWe have already seen escaline (E -- unlike the the common usage of the term, which is short for Ecstacy, which is supposedly MDMA) in the above section. A number of analogues are possible by replacing combinations of the 3,4,5-methoxys with an ethoxy. These are summarized in the following table. The strange naming of SB refers to the fact that it is 3,5-bisescaline and that the ethoxys are symmetrically placed on the ring. ASB is the asymmetric version; it is this PiHKAL entry in which Shulgin describes the naming. In chemical nomenclature the "s" in "bis" means, to paraphrase from Shulgin in the ASB entry, that there are two somethings (ethoxys) attached to something (phenethylamine), rather than three whatevers (biescaline, two escalines). Likewise, TRIS is 3,4,5-triethoxyphenethylamine, or 3,4,5-trisescaline.Analogues of these have also been made by replacing one or more oxygen (as part of a methoxy or ethoxy) with a sulfur atom. The following table lists the relevant substances to be found in PiHKAL:
The 3C- version of E is given a separate entry in PiHKAL, as 3C-E.
2.1.4 Other Mescaline DerivativesTMA proved about twice as potent as mescaline. Shulgin reasoned that perhaps even longer carbon side-chains at the alpha position would further increase potency. The result, alpha-ethylmescaline (AEM), proved inactive at the hundreds of milligrams level. A number of longer homologues are discussed in the same PiHKAL entry, and are assumed to be inactive.The methylthio analogues of mescaline and IM (isomescaline) have their own entries: 3-TM and 4-TM, and 2-TIM, 3-TIM and 4-TIM. Two other derivatives of mescaline are included in PiHKAL: The addition of neutrons to the beta-hydrogens (making them deuteriums) gives beta-D, and addition of a methoxy at the beta position gives BOM. 2.2 The 2,4,5 PhenethylaminesThe exploration of the TMA isomers led to the discovery of the magic of the 2,4,5 configuration. As described above, the inspiration for this was mescaline, however the family tree of the 2,4,5-s is so rich that it deserves its own section.2.2.1 The XXXsTMA-2 proved to be positive in effects, at high potency. Shulgin decided to explore modifications of the three methoxy groups, firstly by forming ethoxy homologues. The naming system of these substances reflects the substitutions: for example, MEM is 2-methoxy-3-ethoxy-5-methoxyamphetamine (2,5-dimethoxy-4-ethoxy-amphetamine, MEM). Naturally, there are eight such structures: MMM (TMA-2), MME, MEM, MEE, EMM, EME, EEM and EEE.Of these, MEM was the most interesting and the 4-position was chosen as the site of a large range of substitutions, leading to a large range of now-famous compounds. The first substitution is the next in the homologous series, 2,5-dimethoxy-4-propoxyamphetamine (MPM). Shulgin also made versions with isopropoxy, butoxy and amyl groups in the 4-position : these are described in the PiHKAL entry for MPM. All were abandoned due to reduced potency.
2.2.2 DOM and its 4-Substituted DerivativesClearly the 4-position is important to the activity of these substances. To test whether TMA-2 and MEM were intrinsically active, or whether some metabolite was the active substance, Shulgin replaced the 4-MeO of TMA-2 with the more resilient methyl group to form a "DesOxy Methylated" version, DOM : see p. 53 of Book I for the story. DOM, 2,5-dimethoxy-4-methylamphetamine was found to be a very potent psychedelic and forms the prototype for many structural explorations.The following table lists the substances described in PiHKAL that are derived from DOM by substitution at the 4-position. Phenethylamine analogues, versions with methylthio rather than methoxy in either the 2- or 5-position, and beta-substituted PEA versions are also listed.
As you can see, a lot of fun has been had working with the 2,4,5 pattern! There are several further derivatives not included in the table. Versions of these compounds with the substitution in the 5-position instead of the 4-position are called the "meta" series. Two such compounds have entries in PiHKAL: META-DOB and META-DOT (DOT is a synonym of ALEPH). Likewise, ORTHO-DOT is the 2-methylthio version of TMA-2. The 2,5-bismethylthio (two MeS groups) version of DOM is included in PiHKAL as BIS-TOM. Adding two hydroxys to the amine nitrogen in 2C-T-2, 2C-T-7 and 2C-T-17 gave HOT-2, HOT-7 and HOT-17. The potency was seemingly unaffected by this substitution, indicating that perhaps the OH is removed metabolically (or that one is added metabolically to the 2-T series); see the entry for FLEA for an interesting discussion of this. Placing two methyls on the amine nitrogen of DOI gave IDNNA. The N-methyl version of DOB is also included, as METHYL-DOB. Changing the ethylamine of DOM to cyclopropylamine yields DMCPA. Building a methylenedioxy ring across 3,4 gives DMMDA, although this could equally be considered a derivative of MDA. As an experiment to investigate an extreme reaction to 5-TOM in "George" (described in chapter 36 of Book I), a compound called TOMSO was made by putting a methylsulfinyl group in the 5-position of DOM (or 5-TOM).
Since these compounds were inspired by the 2,4,5-substitued TMA-2, the 2,4,6-substitued TMA-6
which showed similar promise to TMA-2 ought also to
act as a model for a family of compounds. Only two of these are
described in PiHKAL : 4-methyl-2,6-dimethoxyampheamine, or pseudo-DOM, and
4-isopropyl-2,6-dimethoxyphenethyamine, pseudo-2C-T-4. These substances are often written
with
2.2.3 The Classic Ladies and the GsThe alpha-ethyl homologue of DOM and 2C-B, called ARIADNE is the first of Shulgin's "Classic Ladies" series. This series, described in the ARIADNE entry, consists of the ten unique homologues of DOM obtained by subsituting hydrogens (one at a time) with methyls. Not all of these have been synthesized and tried in humans. The Ladies (with links for those which have been tasted) are: ARIADNE, BEATRICE, CHARMIAN, DAPHNE, ELVIRA, FLORENCE, GANESHA, HECATE (DOET), IRIS and JUNO. There are suggestions of anti-depressant activity from ARIADNE and a large number of derivatives of this substance are mentioned her PiHKAL entry.A number of modifications of GANESHA are described in PiHKAL. Making a ring with the 3,4 carbons using trimethylene, tetramethylene, or norbornyl gives G-3, G-4, or G-5. One more carbon produces the double-benzene-ringed napthyl group : the compound is then 1,4-dimethoxynapthyl-2-isopropylamine, or G-N. Phenethylamine analogues of these are also described : 2C-G-3, 2C-G-4, 2C-G-5 and 2C-G-N (1,4-dimethoxynapthyl-2-ethylamine).
2.3 Substances Derived from MDAAnother psychedelic phenethylamine of importance is MDA. This consists of an amphetamine backbone with a methylenedioxy (-O-CH2-O-) joining the 3,4 phenyl carbons to form a ring:
A large number of the substances described in PiHKAL are derived from this basic structure. Even after categorizing them all below, I still find it difficult to go from the names of these substances to their structure : too many Ms and Ds! It is worth listing them here for reference, anyway. 2.3.1 Simple N-Substituted MDAsA large proportion of the MDA-derived substances in PiHKAL have one or more substituents on the amine nitrogen atom. The singly-substituted amphetamines are as follows:
Only one of the above has its 2C- version listed in PiHKAL: this is MDPEA, the phenethylamine analogue of MDA. A number of N-substituted compounds are also listed in the next section, and in section 2.3.4.
2.3.2 Derivatives of MDMAMDMA, of course, is famous for its unique action and has seen extensive (now underground) use in psychotherapy, as well as becoming popular among dance enthusiasts and a media favourite "evil designer drug". Shulgin investigated a number of modifications to the structure in an effort to mediate the undesirable bodily effects of MDMA (see the entry for FLEA, which also contains other interesting stuff). The doubly N-methylated version of MDMA is presented as MDDM. MDMP is the phentermine analogue of MDMA: this has an extra methyl group attached to the alpha carbon. Removing the N-methyl from MDMP gives MDPH. The naming gets more esoteric than that, though. Addition of a methoxy in the 6-position gives MADAM-6, a cheeky name that takes advantage of the nickname of MDMA, ADAM. The N-hydroxylated version is called FLEA (as in HADAM/"had 'em")! One wonders if the cook tasted his creations shortly before naming them. Finally, J (see section 2.3.4) is a fairly close isomer of MDMA.
2.3.3 MeO-MDAsA number of substances in PiHKAL are derived from MDA with the addition of one or more methoxy groups. With the exception of MDMEO, which is N-methoxy-MDA, all methoxylation takes place on the benzene ring. The following table lists the amphetamine versions of these. Note that the methoxy position listed refers to a position in MDA; when named according to the proper rules of nomenclature (e.g. in the PiHKAL Short Index), some substances have their methylenedioxy at 4,5 instead of 3,4 and hence 2-MeO and 6-MeO are interchanged, and 5-MeO becomes 3-MeO.
Several derivatives of these amphetamines are included in PiHKAL. LOPHOPHINE (so-named due to its expected presence in trace quantites in peyote, Lophophora williamsii) is the 2C- version of MMDA. MEDA is the result of changing the methylenedioxy ring of MMDA to an ethylenedioxy. METHYL-MMDA-2 is the N-methylated version of MMDA-2, whilst 4T-MMDA-2 is its methylenethiooxy analogue. 2T-MMDA-3a is the MeS version of MMDA-3a. MMDA-3b is the isomer of MMDA-3a obtained by switching the 4-position end of the methylenedioxy group and the 2-methoxy group, to obtain 4-methoxy-2,3-methylenedioxyamphetamine.
2.3.4 Alpha Homologues of MDAAs an amphetamine, MDA has a methyl group at the alpha position. PiHKAL includes a number of derivatives with other groups attached to the alpha group. MDMP and MDPH both have an extra methyl at the alpha position, as we have already seen in section 2.3.2.The alpha-ethyl and alpha-propyl homologues of MDA are known as J and K (see METHYL-K) respectively. Their N-methylated versions are METHYL-J and METHYL-K; the N-ethylated versions are ETHYL-J and ETHYL-K. See the entries for METHYL-J and J for the bizarre story of the naming of these compounds. 2.3.5 Other MDA DerivativesA further two compounds in PiHKAL utilise the methylenedioxy ring. 2-Br-4,5-MDA has its structure well-specified by the name, and is untasted. BOH is beta-methoxy-MDA : see section 2.4.1.
2.4 Alternative Groupings and Miscellaneous Compounds2.4.1 BOXesShulgin lists a number of compounds with a methoxy or hydroxy group attached at the beta position. All of these have been discussed above as derivatives of mescaline (BOM, DME), DOM (BOD, BOHD, BOB) or MDA (BOH : the "H" refers to "homopiperonylamine" [i.e. MDPEA], see the entry for METHYL-J). The idea with these substances was to emulate the relationship between dopamine and norepinephrine (beta-hydroxydopamine): see the entries for BOD, DME and BOH for discussion.
2.4.2 BenzofuransAs an excuse to attend a marijuana conference in Sweden (see chapter 10 of book I, and the entry for F-2), Shulgin synthesized two amphetamines with (mono and di-) methylated furan rings fused to the benzene ring. These were supposed to vaguely resemble THC, and were called F-2 and F-22.
3.0 Index to the PhenethylaminesThe following is a list of all the PiKHAL substances. Included are links to the most relevant section of the tour presented above, and to the PiHKAL entries supplied by Erowid and The Lycaeum. As noted in the introduction, the Lycaeum has the structural formulae available online.
ChangesThis file is copyright 2000 rkundalini. Please distribute (unmodified) freely. Given the number of chemicals referenced in this document, there are bound to be mistakes, improvements, etc that must be made. To keep things organized, please do not modify this document yourself. Corrections, suggestions and so on are welcomed, send them to rkundalini@hotmail.com.
Version 1.0 (17 Mar 00): Initial revision. This text was taken from The Forbidden Fruit |
(alpha) and 
(beta), starting from the right. The
most interesting compounds are those with the phenyl attached at the
beta position (a la beta-phenethylamine). Some alpha-phenethylamines
are discussed in the 
- as the prefix: this is the greek
letter psi, not gamma as used in the online PiHKAL indices. The entry
for 