Recently I’ve seen a lot of discussion about hexahydrocannabinol (HHC) and CBN being derived synthetically from d8 and d9 THC using reagents like palladium on carbon (Pd/C), platinum on carbon (Pt/C) and others like it. However, I haven’t seen any explicit discussion of these reagents in a chemical sense; electrons, orbitals, coordination chemistry, reaction conditions and most importantly, cleanup! I figure since it’s in my wheel house, and the chemistry is fascinating, I would share my knowledge of it so we can all learn how to make better and safer products.
Let’s start with what caught my attention: is hydrogenation of THC to HHC. Below is an arrow pushing mechanism of THC being converted to HHC using palladium on carbon (Pd/C). This reaction uses an activated carbon functionalized with 5%-10% Pd on the surface. The reason for using carbon instead of bulk metal is because the surface is where the chemistry happens, and a lump of metal would be wasteful; palladium is ~50,000x rarer that its 3d transition metal counterpart nickel. Hydrogen is used as a stoichiometric reagent in this case.
Figure 1. starts with a Pd/C surface with a Pd (0) species. The cannabinoid coordinates with the Pd at the alkene moiety, oxidizing the Pd to Pd (II). One molar equivalent of hydrogen gas then coordinates to the Pd as hydride ligands. The cannabinoid pi ligand bond attacks one hydrogen ligand, and then the second. The ligand then dissociates, yielding a HHC molecule and a regenerated catalyst.
This is a very general mechanism of how these systems are working. I omitted a lot of things, including counterions, intermediates, and other small details for clarity’s sake; but believe me, there is a lot that can be added. I would also like to say this is not necessarily an official mechanism and there can be more steps but does capture the reaction in at least broad strokes.
I’ll be posting more mechanisms, side reactions, coordination chemistry as I go; but it takes time to make these figures and verify the chemistry I present is as accurate as i can make it.
Anyone can chip in if they like with questions or corrections. Please recruit accordingly if you wish!
And I’m not sure that it is completely correct as it doesn’t explain the absolute syn addition of H2 to an alkene.
I think one Pd coordinates H2 in “sideways” manner while another neighboring Pd coordinates the alkene, allowing the H2 to be added in concert over the double bond.
I think the addition/elimination type mechanism à la Buchwald-Hartwig may not be applicable to catalytic hydrogenation.
This is actually called re/si (pronounced REE/SAI) where you have the different faces where you can attack. The Pd coordinates above or below the pi bond; think above and below the double bond as you see it on the screen, the top is the re face, bottom is si. Depending on the sterics of the molecule you’re working with, you will have different re/si selectivity. Because THC is enantiomerically pure, you will only have two sets of diastereomers form, instead of four if your thc was racemic.
The purpose of mechanisms is to see how the electrons are moving so you can tune your reaction chemistry, add reagents etc. Often mechanisms will use double barbed arrows showing 2 electrons moving instead of single barbed to show one (I showed 1 in this case). If we could actually see the electrons, most mechanisms would be one electron at a time. But two barb arrows are more concise, and still convey the message. Instead, think of a mechanism as a statistical representation of where most electrons go, not a road map.
But the only way to explain the absolute syn addition of H2 to an alkene is to invoke a four electron transition state. At least that is how it was taught in the past.
It depends on the addition, that sounds like an alcohol addition, not a hydrogenation. It also sounds like a concerted reaction, this is stepwise. Again, broad strokes, I omitted the chiral center on the THC, so any bond that doesn’t have a dash or wedge is assumed to be racemic, (ignores geometry)
There’s a lot of ways to do this mechanism in particular (hydrogenation/reduction very disputed), I am more familiar with coupling reactions (suzuki-muiyara coupling) so there’s some influences of that there.
The first mechanism is also single metal-centric, and doesn’t rely on a surface. It depends on how the palladium is dispersed, if the surface has single palladium atoms on the distributed, or palladium nano particles that act similar to an electrolytic surface. It’s likely a blend of both.
The mechanism you propose is applicable to homogenous catalytic hydrogenation. In the case of the heterogeneous version with metallic Pd and to explain the overall and exclusive syn addition, something akin to a 2+2 cycloaddition has to be invoked, I think.
Actually, this working model invokes sequential addition of hydrogen:
While the in situ generation of hydrogen is rather elegant, it does add at least two more layers of complexity to any pondered large scale application.
In the case of HHC from d8/d9, the ease of catalytic hydrogenation really lends itself to bottled hydrogen, or generation on demand.
Electrodes and electricity at large scale is asking for trouble, IMHO.
Electro-synthesis is typically easier. You just need a pot and a bulk sized anode and cathode. You generate the gas at the catalyst surface itself in near stoichiometric quantity. You are talking about DC voltages and low currents to drive reactions as well.
It used to be quite hard and for that reason a much underutilized technique. This is rapidly changing much due to IKA’s ElectraSyn platform.
I highly recommend checking out some of Phil Baran’s talks on YouTube. There’s also an extensive series of lectures on Organometallic Chemistry in general, also out of Scripps.
you ever use an electrosyn? we had purchased one in like 2018 and had all these great ideas we never got around to trying. I assume its sitting (brand new, in its little lunchbox) in storage somewhere. kind of insane because it was at least $5k if not more like $7k
