I am new to the CBD to D8 conversion and I am trying to figure out what characteristics are most desirable in an acid when choosing one. I have heard of people using HCl, pTSA, etc. but I don’t know why someone would choose one over the other.
I have ran the reaction with various acids but only because of literature that I have read. I am really just trying to understand the theory more.
Definitely all here to be searched. PTSA seemed to be the favored choice. See the d8 sop threads.
There are many variables from my experience. Solvent choice, batch size, workability of the catalyst, desired outcome of %'s. I’ve ran this conversion with 3 different solvents (heptane, hexane, toluene) all with ptsa in various sized batches. Also, some catalysts are harder to neutralize and remove from the crude than others. It probably will come down to whatever you are comfortable with working with. Main thing is to be CAREFUL in your lab.
I think the most important variable is temperature, and the ability to maintain desired target temperature.
Cyclizations are generally pretty exothermic. Things like rate of addition can have a big effect on your ability to maintain temperature.
Also starting with a true sop that will get you to your desired cannabinoid %.
@mitokid raised an important fact. Heat and controlling the exothermic spike is of great importance and really dictates the run.
I think the MOST important thing is the ability to purify the reaction mixture. If you can’t clean it up properly, you are creating and selling poison. It’s one thing to dabble in synthesis, it’s another thing entirely to dabble and sell said product to another human to inhale.
Very true. I assumed most operators vacuum distilled their crude cyclization products, arriving at a close to 100% d8/d9 mixture.
I was only trying to provide my two cents as to what I believe is most important when minimizing formation of d8, apart from the critical choice of Lewis acid and solvent, of course.
I think the most important part is to have fun and be yourself
I should reiterate, the reactions I have run have been successful. Ive been using pTSA and been getting great results. I was just wondering about the theory. Like how did someone discover that pTSA would work so well and why not any other acid.
From a mechanistic point of view, the cyclization is pretty easy to understand; The isopropenyl group needs to get activated by either a protic acid (Brønsted-Lowry), or an electron-deficient atom center of a “bigger” reagent such as ZnBr2 (Lewis “acid”).
In the protic case, think of the proton as being added to the double bond and in principle, the proton can become attached to (CBD numbering) either C8 or C9, forming a positively charged carbocation at C9 or C8.
In the first case, the carbocation is said to be primary, and in the other case the carbocation formed is tertiary. Tertiary carbocations are much much more stable than primary carbocations and you will in practice only form the tertiary carbocation which now forms a chemical bond with one of the free electron pairs of either of the phenolic hydroxyls. D9-THC has been formed.
Since the ring closure is of an intramolecular nature, these two discrete events can virtually happen simultaneously in a pseudo-Sn2 fashion. The “lifetime” of the carbocation is very very short.
In the case of a Lewis acid, think of the metal center as co-ordinating to the double bond, the electron density of the double bond shifted towards the metal, and again, you have created (a little) positive nature at carbons 8 and 9, and again, 8 is more positive than 9, and ring closure occurs as above.
From this description, one can draw the conclusion that you don’t really need a fully developed positive charge for the cyclization to occur.
Protic acids are of type HX, carboxylic acids, sulfonic acids, phosphoric acids, etc. Anything that can provide a proton, H+. HX is often unnecessarily strong and there can be side reactions. Organic synthesis is very much about tuning the combined substrate/reagent/catalyst reactivities so you create what you want, while suppressing competing reaction pathways.
Sulfonic acids just happen to be very versatile and easy to handle protic acids. Now, why pTSA?
This is where it gets interesting and very few chemists know the backstory. It is because of an artificial sweetener, saccharine, that pTSA found itself on the throne of protic acids, and it all started towards the end of the 19th Century, when Organic Chemistry was still lying in its cradle.
Can you figure it out?
So toluene was originally sulfonated to create pTSA and oTSA which was then converted in the end into saccharine and p-sulfamoylbenzoic acid which had to be separated. Interesting how it was a precursor to a widely used artificial sweetener. I’ve heard that it was “soft banned” in the late 70’s for causing bladder cancer in rats but I fact checked that and it turns out it was discovered that rats metabolize it differently than humans so it was brought back as good old fashioned sweet n’ low. I also read that Teddy Roosevelt was told that it was dangerous when it was first being widely used and he remarked, “Anyone who says saccharin is injurious to health is an idiot.”
This is what I’ve discovered
Great explanation sir 
I have always taken this statement as the basis of all that I do but at the same time
I am becoming aware that the urge to produce is larger than the urge to understand what we are doing and how to do this as safe as possible I am basically lost at the moment in how to proceed with advise and teaching
Tough times
Exactly! Only problem was that pTSA was a major side product and they needed to find uses for it. It was heavily promoted as a general multipurpose acid catalyst in the early and mid 20th Century according to my now very old or dead old country mentors.
Basically, pTSA is a byproduct of saccharine production. It’s an excellent acidic catalyst, not too hygroscopic but it has that very pesky crystal water that sometimes complicate matters.
I always liked BSA, pTSA without the methyl group. It can be distilled and you end up with very dry, very pure BSA.
BSA acid have a cas number ?
[98-11-3]
November 3rd, 1998