Kava Science Which kavalactones are actually "double bonded"?

[verticity]

I'm reposting this as it's own thread since I don't know if anyone will see it in it's original location.

I am questioning my sanity. On kava forums people have been referring to the kavalactones DHM and DHK as "double bonded" for awhile. But I have come to believe they are not, in fact, double bonded. Blasphemy!

I'm not a kava expert. I read about "double bonded" kavalactones here, and I believed it, too; it seemed to make sense that DHK and DHM are chemically distinct from the other KLs, evidenced by their heavy effects. But then I went back and looked at Lebot's book, and other academic sources, looked at the diagrams of the molecules, and I did not see these double bonds everyone was talking about, so I was like "what the.." and "but I thought..".

So first, let me explain what those pictures of molecules mean. They are diagrams of organic molecules, which means they are made up of carbon, hydrogen and oxygen atoms primarily, sometimes nitrogen or a few other things; But KLs are just carbon, hydrogen and oxygen. The letter "O" represents an oxygen atom. "C" represents carbon, and "H" represents hydrogen. But also, chemists are lazy, so they generally don't show all the carbons and hydrogens explicitly. Every vertex in a diagram like that represents a carbon atom. The hydrogens are usually not represented at all, but there are hydrogens attached to each carbon atom (that has less than 4 bonds to other atoms), so that each carbon atom has four bonds. It may be bonded to four other atoms, for example, here is methane (showing the hydrogens explicitly) because there is only one carbon atom):

Methane is just a carbon bonded to 4 hydrogens. Like I said, the vertices of the diagrams can represent carbon atoms, so here is propane, explicitly showing the atoms:

(Obviously I suck as an artist) So propane is 3 carbons with attached hydrogens. Notice that each carbon atom is bonded to four other atoms. This is also propane:

There is one carbon at the bend in the line, and one carbon each at the ends of the lines. The hydrogen atoms are implicit.
Now, carbon always wants to form 4 bonds, but some of those can be double bonds, Each double bond counts as two bonds (duh), so carbon can only bond to two other atoms if it is double bonded to something. Example, here is propene:

It has a double bond, represented by 2 lines. This is also propene:

Another thing to know is when you see a benzene ring which looks like this:

Those things that look like double bonds are actually not really double bonds, because the electrons are delocalized over the whole ring, so it's like the whole ring partakes of one big circular bond.

So finally we come to kavalactones. Here is dihydromethysticin:

Lebot's book classifies KLs by whether they have single or double bonds at the locations with the red arrows above. Different KLs have different combinations of single/double bonds at those sites. It so happens that DHK and DHM have single bonds there.
Here is methysticin:

Crappy picture, but you can see Methysticin has a double bond where dihydromethysticin has a single bond, but they are otherwise identical.
If you look at the diagrams of Kavain and dihydrokavain, you'll see it's a similar story.

Did I just blow your mind?

 

[The Kap'n]

Mind blown. Seems we've been using terms that are not only outdated, but incorrect. As I've said before, everything here is subject to revision. Thanks for pointing this out!

 

[sɥɐʞɐs]

Good write up and a step in the right direction of the clarification the community needs on this topic.
Now, if you or anyone reading this, has the knowledge themselves or a chemistry professor to ask...here are a couple things that would be useful to have an official answer to:

- Is there an official term used to describe chemicals that have Dihydro- or Demethoxy- added to them ?
("Saturated" was suggested as a possibility but I don't want to start spreading it without confirmation)

- Does the term "Saturated" and "Unsaturated" in regard to organic compounds correlate with Dihydro- or Demethoxy- being in their name...or does it correlate with whether or not they have a single bond or double bond ? ...and do those two things correlate with each other at all ?
I suppose not, because of DMY on this chart.

- Does the addition of things like Dihydro- or Demethoxy- always equate to a longer metabolism or heavier experience, in psychoactives ?
(example: would a hypothical 'Dihydro-Methamphetamine' have a longer metabolism or perhaps a heavier body load/sedation than regular 'methamphetamine', because of the addition of Dihydro?)

 

[verticity]

• • Some possible terms that could be used:
• Saturated - This is not really an official term, but kind of an analogy with the terminology for fats, where in saturated fats the carbon atoms have the maximum number of hydrogens attached to them that they can, hence they are "saturated" with hydrogen atoms, meaning they don't have double bonds, because if a double bond is taking up 2 of the bonds a carbon atom is allowed to have, then it can't have the maximum number of hydrogens that it could.
  
• Hydrogenated - Similar to saturated. You've probably heard of saturated and hydrogenated fats.
• Single bonded
• Double single bonded - because there are 2 single bonds. Probably too confusing

The prefix dihydro- does correlate with saturation (and not having double bonds) because generally if there are more hydrogens, then there are fewer bonds between carbons, hence fewer double bonds.
Demethoxy- means something different. Methoxy is like a methane molecule with one of the hydrogens replaced with an oxygen, so CH3O-. Oxygen wants to form two bonds, so a methoxy group has to be attached to something. Yangonin is:

That thing on the lower left attached to the benzene ring is the methoxy group. Demethoxy- means something does not have the methoxy group, so DMY is:

In general, I think you can't predict what adding or removing double bonds, or groups like methoxy, will do to metabolism. It kind of depends on the details of which enzyme in the liver is metabolizing it, and exactly how that happens, like the shape of the molecule compared to the shape of the enzyme. I could be wrong about that though.

 

[TheKavaSociety]

mind blown. Kavalactones are nothing by carbon, hydrogen and oxygen? Where is the magic?

 

[verticity]

@verticity - I'm sure glad you brought this up, I've been puzzling over it for a long time. The traditionally named double bonded kavalactones don't make any sense to me, but I'm not that much of a chemist at this level. Here's all I could find, see if makes sense to you. Page 68 of "Kava, the Pacific Drug":

"Some researchers have tried to classify kavalactones by reference to common characteristics. The simplest method of grouping is one suggested by Hansel (1968), which sorts the molecules according to the presence or absence of double bonds at the 5,6 and 7,8 positions and divides them into two major groups: the enolides, with one double bond, and the deinolides, with two double bonds. This system recognizes that primary chemical differences among the kavalactones involve the presence or absence of these double bonds as well as the presence or absence of substituent groups in the phenyl ring."

I'm not sure why they say there are only 2 categories, since they are talking about 2 double bonds which can be present or absent (the one between the carbon atoms labeled 7 and 8, and the one between carbon atoms 5 and 6) (Note there are actually a minimum of 2 double bonds in all the KLs, but the one in the upper right, and the one connecting the oxygen on the right don't "count" because they are not distinguishing) So there are actually three permutations of 2 double bonds:

• 2 double bonds - Yangonin, Demethoxyyangonin
• 1 double bond - Methysticin, Kavain
• 0 double bonds - Dihydromethysticin, Dihydrokavain

My guess is this is just a misunderstanding that arose from that exact passage in Dr. Lebot's book and the accompanying figure, and got reinforced by repetition.
And of course diplopia is a common side effect of kava consumption.

Ref:

 

[kavadude]

I've always thought we are a bit too quick to attribute the effects of kava to individual kavalactones. Certainly we have enough collective experience to say that most don't prefer the dihydro- variants but as to why, who knows.

 

[verticity]

"Correlation with information gained from ethnobotanical studies shows that drinkers do not appreciate a high percentage of DHK and DHM..." (Origin and Distribution of Kava, Lebot, 1989)

And those are the two without double bonds? Now I really am confused!

Well, the point remains that DHK and DHM are in fact chemically similar to each other, and distinct from the other kavalactones, as distinguished by the presence or absence of double bonds, so it still makes sense to group them together, since they have similar subjective effects. It would be interesting if we knew more about the pharmacological effects of yangonin and DMY (with 2 double bonds), to see if there were some trends correlating number of double bonds with effects.

 

[verticity]

So, have we reached a consensus, or are we more confused than when we started?
I'm not ready for the , I want resolution!

Well, I don't know if it's the kind of thing that makes sense to vote on. It is what it is.. But, I guess you're asking should the "official" position of kavaforums be changed to no longer say that DHM and DHK are "double bonded." I believe it should be. But I am just one voice (in the wilderness).

 

[TheKavaSociety]

Well, I don't know if it's the kind of thing that makes sense to vote on. It is what it is.. But, I guess you're asking should the "official" position of kavaforums be changed to no longer say that DHM and DHK are "double bonded." I believe it should be. But I am just one voice (in the wilderness).

And what other term would you suggest?

 

[verticity]

And what other term would you suggest?

They could be described by their effects, i.e. the "heavy kavalactones", or chemically, you could call them "saturated", "hydrogenated", or to be really explicit but verbose, "having single bonds at the 5,6 and 7,8 positions." I like the term "hydrogenated" because it fits in with the prefix "dihydro-". But you would really need to ask Dr. Lebot if there is an official term.

 

[Palmetto]

I am reviving an old thread here. The 6 membered rings in all of the major kavalactones have double bonds not counted in the tallies above. The "backbone" between these rings is double bonded in kavain, methysticin, and demethoxyyangonin, but the same linkage is single bonded (saturated) in HDM, DHK, and yangonin. At the molecular level, the double bonds (unsaturation) permits more molecular flexibility and rotation. This property greatly influences binding to biological receptors, chemical packing, and thus water / oil partitioning, among other effects. DMY has some similar receptor binding effects to kavain that are not shared by yangonin, since yangonin lacks a double bond in the backbone, but it does have a fairly similar structure to kavain otherwise. Years ago, I used to exploit the significant differences between highly similar large molecules which only differed in a single double bond.

 

[verticity]

I am reviving an old thread here. The 6 membered rings in all of the major kavalactones have double bonds not counted in the tallies above. The "backbone" between these rings is double bonded in kavain, methysticin, and demethoxyyangonin, but the same linkage is single bonded (saturated) in HDM, DHK, and yangonin. At the molecular level, the double bonds (unsaturation) permits more molecular flexibility and rotation. This property greatly influences binding to biological receptors, chemical packing, and thus water / oil partitioning, among other effects. DMY has some similar receptor binding effects to kavain that are not shared by yangonin, since yangonin lacks a double bond in the backbone, but it does have a fairly similar structure to kavain otherwise. Years ago, I used to exploit the significant differences between highly similar large molecules which only differed in a single double bond.

Interesting. That is the first real explanation I have seen of what the effects of DMY might be like.

 

[verticity]

... At the molecular level, the double bonds (unsaturation) permits more molecular flexibility and rotation. ...

Wouldn't it be the opposite: shouldn't single bonds (saturation) permit more rotation?

 

[Palmetto]

Verticity, perhaps I was thinking of it from the perspective of someone who is a few years removed from the lab. I used to work with lipids (and genes). When they have double bonds in the chain, they have lower melting points and don't pack as closely together, thus van der Waals forces are lowered, thus the hydrophobicity actually lowers (though modestly). Do you currently work in a lab. You seem to have pretty good knowledge of chemistry.

 

[verticity]

Verticity, perhaps I was thinking of it from the perspective of someone who is a few years removed from the lab. I used to work with lipids (and genes). When they have double bonds in the chain, they have lower melting points and don't pack as closely together, thus van der Waals forces are lowered, thus the hydrophobicity actually lowers (though modestly). Do you currently work in a lab. You seem to have pretty good knowledge of chemistry.

I don't currently, but I studied gas phase physical chemistry in grad school. I guess that's why I think of the molecules rotating independently in space. But I think the van der Waals forces are increased by the presence of double bonds, because of the increase in polarizability. Maybe the closer packing is due to the fact that double bonds make conformational changes harder, so that if there are not double bonds, the fats can wiggle around and fit together more efficiently. Lipids was not my field of expertise, but van der Waals forces sort of was, so I'm just guessing here.

 

[Palmetto]

In lipids, which are definitely different than KLs, the fatty acid chains are relatively straight when they are saturated, hus they pack together more neatly than when they are kinked by a cis (double) bond. The closer packing increases van der Waals forces and raises the melting point. Unsaturation increases the levels of membrane fluidity, so I tend to associate double bonds that are not part of a ring with greater fluidity, but I should rethink that perhaps for chemicals I am not as familiar with.