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THC Chemistry

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Shulgin writes of the ten THC isomers


Date: Sat, 21 Jan 1995
From: Alexander T. Shulgin
To: Carl Olsen
Subject: old letters


Hi:

I think these are the two files that you wanted.  It is awful 
to lose stuff from the hard disk, when there is no one else to 
blame.

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

olsen-01.ats

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

Hello Carl:

Thanks for the letter.  Let me see if I can answer your questions 
without waiving my hands around.

(1)  How many isomers are there of the THC molecule?

There is delta-1 THC (using a different numbering system, this is 
also known as delta-9 THC).  It has two asymmetric centers, and 
so it can exist in a trans- or as a cis-form (known as 
stereoisomers) and each of these forms is resolvable into a 
dextro- and a levo-component (known as optical isomers).  Putting 
this into a box form, you have:


                    trans-pair (stereo)         cis-pair (stereo)


     dextro-           d-(trans)-delta-1          d-(cis)-delta-1
     (optical)              THC **                     THC


     levo-             l-(trans)-delta-1          l-(cis)-delta-1
     (optical)              THC *                      THC


which adds up to four isomers.

There is also delta-6 THC (same as delta-1(6) THC or, with a 
different numbering systems delta-8 THC).  Using the same square 
as with the delta-1 isomer, we have:


                    trans-pair (stereo)         cis-pair (stereo)


     dextro-           d-(trans)-delta-6          d-(cis)-delta-6
     (optical)              THC                        THC


     levo-             l-(trans)-delta-6          l-(cis)-delta-6
     (optical)              THC                        THC



which totals another four isomers.

There is a third isomer explicitly named in the law, not a 
natural material, but a laboratory product that had been studied 
in the early days of the chemistry of these compounds.  This is 
called delta-3,4 THC (or delta-6a,10a THC with the other 
numbering system).  Here the two optically active carbon atoms 
that allowed the cis-trans argument now carry the double bond 
(the meaning of the term delta) but a new optically active site 
has been opened up at the 1- (9-) position.  So there can be a 
dextro-form and a levo-form (optical isomers) but no cis- or 
trans-pairs.  This totals to another two isomers.  Thus the 
answer to your first question, there are ten possible isomers of 
THC to be considered in the halls of law enforcement.

(2)  What is an isomer?

That depends upon who you ask, and in what context.  Literally, 
iso- means the "same", and -mer is from meros, meaning "part."  
In common chemical usage, it is generally taken to mean that the 
same atoms are there (in terms of which elements and how many of 
them), but they are just hooked up differently.  And when there 
are describing (or limiting) prefixes, they emphasize just how 
these different hookups are most readily recognized.  
     
Stereoisomers are distinguished by the differences in shape.  
Think of a hand in a five-fingered rubber glove, making all kinds 
of different forms, but always with the same amount of hand 
inside the glove.  A fist shape and a splayed finger shape would 
be stereoisomers.

Optical isomers are distinguished by their mirror-image 
relationships.  Two molecules not superimposable but are in every 
other way identical.  Put a rubber glove on your right hand, and 
another on your left.  They are identical, except that cannot be 
superimposed.  One is the mirror reflection of the other.

Positional isomers are defined as have certain groups as being 
over there rather than over here.  Consider a conventional rubber 
glove (the thumb-shaped covering at position one) and then 
another with the thumb position where the third finger usually 
is, and the third finger position at the thumb's location.  These 
are positional isomers, with the finger positions being the 
rearranged factor.

The authors of the law, and thus the DEA, are quite inconsistent 
in the use of this term.  Since you have the Controlled 
Substances Manual, check out the first full paragraph on page 226 
for some insight into this confusion (page 212 if you have the 
first edition).

(3)  Is delta-9 THC an isomer, or does it have isomers of its 
own?


Look up at the first box.  All for named items are isomers of 
delta-9 THC (the trans- and cis-pairs, and the optical isomers of 
each pair).  Thus delta-9 THC can exist in any of four isomeric 
forms.  This is pretty close to saying that delta-9 THC has its 
own isomers.

But, in common parlance, the term delta-9 THC is very often used 
for the natural component of cannabis, the active component, and 
this is explicitly the trans, levo-isomer of delta-9 THC.  This 
is the lower left isomer in that box, the one marked with a "*".  
If this is the sense in which the term delta-9 THC is used (and 
it is so used frequently and casually) then it is an isomer, the 
natural isomer, the one with the * above.

The answer to this question depends exactly on what the asker has 
in mind when he uses the term delta-9 (or, delta-1) THC.  
Remember, that the two names are synonymous.

One final caveat.  The delta-9 THC that is the material used in 
the Schedule II drug known as Dronabinol is something yet 
different than any of these.  It is a synthetic material, and is 
isolated as the trans- material, but I do not believe that it is 
resolved into its optical isomers.  Thus, in this context, delta-
9 THC is a 50:50 mixture of l-(trans)-delta-9 THC and d-(trans)-
delta-9 THC.  This is a 50:50 mixture of the one * and the two ** 
things in the first box above. 

To summarize:

When the term delta-1 (delta-9) THC is used to represent the 
active factor of cannabis, it is the isomer with the one *.

When the term delta-1 (delta-9) THC is used to represent the 
active component in the Schedule II drug, it is a 50:50 mixture 
of the one * and two ** isomers.  

When the term delta-1 (delta-9) THC is used to represent the 
chemical concept without stereo- or optical-designations, then 
the term embraces all four isomers in that first box.  

Hope this helps.  It is a one hour lecture distilled down into a 
ten minute note.

Sasha

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

olsen-02.ats

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

Hi Carl:

I have just now been looking with more care at the package insert
that accompanies the commercial Marinol, Dronabinol, and also the

PDR, and both of them give the chemical name as:

(6a-R-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-
dibenzo[b,d]pyran-1-ol

and the Merck index refers to these commercial drugs as

(-)-delta1-3,4-trans-form

I had assumed, without checking, that the synthetic material was 
the racemate (the two trans isomers in the first of the diagrams 
I sent you.  But the letter "R" in the first name, and the minus
sign "-" in the second name, both attest to the fact that the
synthetic drug (the component of the schedule II item) is indeed
a single isomer.  Thus the term delta-1 THC (delta-9 THC) means 
not three things, but only two.  As a general term, it can be all 
four of those isomers, individually or collectively.  As a 
botanical term, it is the one specific isomer in that collection, 
the l-trans delta-1 isomer (the first "l" is the letter ell, as 
the first letter of levo, or rotating to the left and the second 
is the number "1").  And so is the synthetic.  

And, as to your other question, no, the two isomers cannot be 
isolated from the plant, as only one is there.  

To summarize:

     l-trans- (the letter ell)
     levo-trans
     6a-R-trans
     
all refer to the natural (as well as the synthetic) delta-1 THC, 
that is apparently prepared from optically active starting
materials.

     dl-trans
     racemic trans
     6a without the R but with the trans

all refer to an optically inactive form of delta-1 THC, still
trans, but containing an isomer that is not found in nature, and
that is not in the drug Marinol.

     delta-1 THC can refer to any or all of the four isomers, 
both trans and cis, both levo and dextro.

Sorry about the wrong assumption above.  Hope this makes 
everything clearer.

Sasha

This document Alexander Shulgin

Created 10/8/2000 17:29:36
Modified 10/8/2000 17:42:30
Leda version 1.4.3