Sharing my Research

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Didn't know which section to post this under. I've been around awhile, but for those of you who don't know me I'm a bit of a chemistry freak :)

I just wanted to share some of the results of my real-life research I've been undertaking in my studies over the past 2 years. I'll be presenting this research on Friday and I'm very excited--I've recently had some breakthroughs in the lab (which aren't reflected in the document).

Anyway, I figured most of the science nerds that I know are actually on this website--so why not let you guys get a peep at what keeps me up nights--and wakes me up mornings :)

I'd be happy to field any comments or questions, I'll think of it as practice for Friday (when I'm sure to get ass-reamed by various professors).
 
View attachment THCPoster.pdf
GodZsoN

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Your one intelligent dude.. Thank you for sharing your hard work.. Blessing you with good karma and best luck on your presentation on Friday bro..

Take care,
GodZsoN
 
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A non super imposable mirror image is like your right and left hands. That's what an R or S enantiomer is like. Same stuff--but the mirror image. So if a protein (like the adrenoceptor) has a spot for a right hand to fit, then the left hand won't fit.

This is a synthesis for making the R more than the S, because it fits into one of the slots we're targeting (and the S does not). The drug is an antiarrhythmic agent.

As for the actual organometallic catalysis--I'll have to get back to you (and I will) on that one. I'll need to diagram it out to make it clear (without typing a book about it).
 
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Wild!
What's this mean In layman term.


Okay so here's a pic that should shed some light.

So for a little background just quickly its important to realize that a carbon atom, when attached to 4 other atoms (as it almost always is) takes on a tetrahedral arrangement wherein each of the bonds to the central carbon are equiangular to one another. This essentially looks like a tripod with one atom coming out of the top, and one coming out of each of the legs. The bond angles are 109.5 degrees all the way around.

however, when a carbon atom is attached to only 3 atoms it takes on a trigonal planar arrangement. The angles are again equal and the molecule is arranged as a flat triangle with atoms at the vertices. For this experiment my carbons always have 4 bonds, but in the original molecule one of these bonds is a double bond. A carbon atom with a double bond and two regular bond also takes on a trigonal planar arrangement. When it is in this arrangement and a molecule attacks the substrate to make a 4th bond (and enter the tetrahedral geometry) it can attack from either side of the triangle. as it does this it folds the tripod legs down (and in this case replaces one of the double bonds).

Now its hard to show in a diagram, but if you were to place four different atoms in a tetrahedral arrangement by folding down the legs from either side, you would end up with different molecules. One of them a right hand version, the other a left hand version. If even one of the molecules is the same there is no such handedness to the molecule.

My catalyst draws the first reactant to it, and blocks one of the faces (with one of the substituents), and thus the reaction can only proceed by attacking the exposed face. This controls which hand version I end up with. For reasons that probably won't be clear from this conversation I can change the existing stereochemistry on my catalyst to yield either the R or the S enantiomer in my reaction.

The catalyst itself has this property of "handedness" and that is one of the things we use to our advantage. If a right hand catalyst makes a left hand molecule to excess, a left hand catalyst will make the right hand (usually).

The trick is finding which substituents work the best to drive the reaction to excess in one direction or the other. This is really just trial and error for the most part. If you look at the catalyst in my drawing the portion of the molecule which is linked up to the copper does not change, the rest is varied in different ways until we find something interesting. The dotted triangle over the catalyst represents the first reactant with its face blocked by the catalyst. The second then comes in and as the tripod folds out it actually pushes itself off of the catalyst and frees it up to do the same thing again.

This idea of stereochemistry and handedness is actually very important to drug creation and research (and materials in general, of course). It is also very difficult to pull of a 100% enantioselective reaction. Most anyone who's figured out a way to do it has won a Nobel Prize, and that's because it is so important.

You may have heard of thallidimide, it was a drug back in the day that was for nausea and things like that I believe. Not sure which, but one of the enantiomers worked like a charm--the other enantiomer made pregnant women bear children with flippers for arms. This was the drug that actually led to the discovery of this "handedness" property, not surprisingly.

Nowadays we understand that protein structure, and especially binding sites, work only on certain stereochemical centers. If its not the right arrangement, it won't work.

Many artificial sweeteners are simply the wrong handed version of sugars--which your bodies proteins cannot break down, and thus they are flushed out.

Right now in my research lab what we're essentially doing is trying to make these drugs cheaper. Right now it is expensive to separate the enantiomers so that the correct one can be administered. Also half of the yield is lost immediately due to it being the wrong handed version. Doing it this way we can cut costs dramatically.

I'm working on these antiarrhythmia agents, but most of the research group is at work on cancer and HIV drugs.

The overall goal is to discover novel ways to direct these tripods in the direction we want them to go. I should also definitely take a moment to acknowledge that none of this would be possible without my absolutely genius professor. What you're looking at is my application of his knowledge, not me discovering something on my own.

I've had an opportunity to direct much of this research and to make changes, decide new paths, and so on--but the original idea of how to undertake all of that research is his. I won't name him for obvious reasons, but I will say that sometimes your taxes DO go to important work, hell most of his stuff is paid for by grants that he earns on his own, though.
 
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Dunge

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Nice explanation on state of the art O chem.
I have some questions about how test labs are doing THC assays.
I am also confused about the resultant percentages reported.
When the concentration of ANYTHING is 20% of a sample, this is a huge fraction.
It seems unlikely to be 20% of dry weight.
Perhaps as a function of soluble oils?
Can you offer anything on this?
 
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I think that 20% of dry weight is probably not too far off--when we're getting into 30% I start having my questions as to what the procedure is.

I've often wondered at the procedure, and have recently begun questioning how these newfangled IR detectors work (the assay from the machine that takes 90 seconds to spit out a %). In my studies IR has always been a qualitative test, to tell you what you have not how much--but I guess you could maybe look at signal strength to quantify--if you were doing some mad extrapolation.

Its important to remember where the THC is--its in the resin glands for the most part (there is definitely some in other tissue as well, though). These resin glands are tiny and they are all over (on the insides of buds as well). This becomes, very quickly, a surface area type argument. Whe we get smaller and smaller with our structures we can fit more and more into them. As a for instance, due to its extremely tight packing, each cell in your body contains at least 6 feet of DNA (were it to be stretched out flat), sometimes 12 if it is getting ready to divide. Yes, every single cell.

So you see that amazing things are possible when we get down to microstructure--this is not as potent an effect at the trichome level, but it is a similar one.
 
ttystikk

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So this IS a similar concept to that of 'inverse sugar', where the handedness is reversed- leaving a substance that acts and tastes like sugar, but can't be digested.

Thallidamide babies were all the rage for awhile, until they got a handle on what happened. Now, I hear they're reintroducing thallidamide... with a stupid warning label that says not to go anywhere near women who might become pregnant. How the hell are you supposed to do that on a subway at rush hour? When will they ever learn?

I'm glad to see that at least some tax dollars are going to good use- at least the last penny. Do we really need another $10 billion dollar bomber? Really? I'd love to see what people like you could do with coin like that!

I've been following you for a good bit now- you're one of the few people who can consistently stretch my mind to new ideas and ways of thinking. As I get older, I find that's ever more of a rare pleasure.

Keep up the good work, brother.
 
ttystikk

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Pulling out to the BIG PICTURE for a moment, this kind of thing is what I take as incontrovertible proof that all living things on this planet are related, from microbes to elephants. We all eat and produce sugar of the same 'handedness', and we all use ATP of the same 'handedness.' This didn't come about by chance or accident- it's built into our very biochemistry.

Kind of makes you feel at one with the world, doesn't it?
 
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I thought I'd just mention another cool thing.

The reason why the molecules take on the specific geometries that they do about a central carbon is due to both electronic repulsion, and something called steric hindrance.

There is electronic repulsion because each substituent molecule has electrons zooming around it and these like to spread out. In o-chem we call this sharing of electron density. The electron density will do ANYTHING that it can to equilibrate itself and spread out the charge.

Steric hindrance simply means that only one thing can take up any one space. When you see a CH3 group in a molecule you probably don't think much of it--it's usually represented as this tiny little group hanging off.

In reality this is a huge object on the micro scale. Think of the tripod above with the top connected to the rest of a molecule and the three legs holding hydrogen atoms. Because these bonds are all free to rotate, this is actually a big spinning (fast) tripod hanging off the end of a molecule. We think of it as small, but it can get in the way, and we call that steric hindrance.

It's the same thing we take advantage of during the catalysis. The steric hindrance of the catalyst prevents the 2nd substrate from attacking on an angle at the hindered face.

If you think about it, the tetrahedron is the best structure for spacing out 4 things around a sphere. The triangle is the most spread out you can be with 3 (again equiangular). CO2 is a linear molecule as it's holding on to two things only (and they go to opposite ends of the central carbon to spread out that density). You can end up with different arrangements as it gets more complex. For instance a carbon with two substiuents and a free electron pair will take on a "bent" arrangement. Really this is just the triangle arrangement with one of the vertices being replaced by an electron pair. The molecules is sharing the density in the same way, except we view it as a bent bond (because there is no "bond" to the electron pair, but it still pushes the other two groups away).

Figuring all these angles and whatnot is a big part of what organic chemists do. Just thought some people might find this interesting--I sure did when I first started learning about it. I had never conceived of the wild geometries involved in molecules. Imagine, each carbon in every carbon chain is conjugated in this same way (gets weird when you move into ring structure so I won't go there). We think of a carbon chain as a "straight chain".

Newsflash--it's not :)

This is all a representation of valence shell electron pair repulsion theory or VSEPR. You can read more here http://en.wikipedia.org/wiki/VSEPR_theory

If you scroll down that page to somewhere in the middle, you can see many of the different geometries that occur. I promise that once you're looking at it, a lot of this will seem a bit less gobledie-gook-ish (if you're geometrically inclined). If you look at the ball-and-stick models where the electrons are represented as yellow balls, it really clears it up and shows you how some of the more interesting geometries (like see-saw) form.
 
ttystikk

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I've seen lots of stick and ball models, and taken the basic chemistry class- which entitles one to say 'I have NO idea how that works!'- and it's nice to have you put some meat on those bones.

Why does water- H2O- not follow the seemingly obvious trend and have the two hydrogens straight opposite of one another? And one more that pertains to what we all like to do here; what exactly does H2O2 look like, and does its structure have anything to to with its properties, or are they just strictly a consequence of that molecule being so unstable? I figured I'd start with little molecules- we can work our way up to benzene rings and peptide chains later!
 
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I've seen lots of stick and ball models, and taken the basic chemistry class- which entitles one to say 'I have NO idea how that works!'- and it's nice to have you put some meat on those bones.

Why does water- H2O- not follow the seemingly obvious trend and have the two hydrogens straight opposite of one another? And one more that pertains to what we all like to do here; what exactly does H2O2 look like, and does its structure have anything to to with its properties, or are they just strictly a consequence of that molecule being so unstable? I figured I'd start with little molecules- we can work our way up to benzene rings and peptide chains later!


Now these are some questions I can answer!

As I mentioned before electron pairs (called lone pairs) can take up one of these "slots". Oxygen has two of these electron pairs (4 total) in its valence when it has made two bonds. Each electron pair generally represents a place where a bond could be made as a little aside, however Oxygen typically only likes to make 2 bonds, with any further bonds usually being very unstable and short lived. Should be noted that oxygen doesn't particularly like having only one bond either--it tries to have two as hard as it can given a set of conditions.

Moving on.

Because there are two electron pairs, and two bonds (to the hydrogens), what you are seeing is a tetrahedral arrangement with two of the legs missing. The bond angle isn't 120 degrees as you'd see with a trigonal arrangement, it is about 104.5 degrees (the compression from 109.5 is due to the electron pairs, they really don't like to hang out next to each other--a proton (hydrogen) and an electron are equal in charge magnitude, thus because there are more electrons than protons the charge gradient causes the protons to hang out closer than the electron pairs. If oxygen had only one lone pair in its valence we would expect to see 120 degree bond angles, because the repulsion from any one constiuent to the next (including the lone pair ) would be equaled out through the molecule.

A way to figure out if a molecule is "polar" or not is to decide what the geometry is, and then draw vectors in accordance with those degrees (in a 3d plot) facing the most electronegative atoms. In this case we have a vector going up and to the side at 104.5 degrees, and a second coming in the opposite direction to the side but still going up. The vector to the side is cancelled and with end up with a net dipole pointing up and away from the oxygen. If you do this with a nonpolar molecule like CH4 (the carbon is the more electronegative and so lines will be drawn towards it) what you end up with is a net zero vector. The vectors from the "legs" of the tripod cancel each other out in terms of side to side motion (looks like a helix if u draw it out) but leave you 1 unit down below the central atom. The last vector brings you straight back up one. It might seem crazy and tedious--but this is how it works :)

On to H2O2:

This molecule has more than one central atom, so to speak. So the calculation is a bit different. In this case we're looking at two oxygens hooked up to each other in the middle, with each oxygen hanging onto a hydrogen.

For this case we look at the geometry about each oxygen molecule. Quickly we realize that each oxygen is connected to the same amount of things (and with the same number of lone pairs) as in water, above. This is known as the hybridization state about the central atom. What you're looking at here is a tetrahedral arrangement about each oxygen. the bond angles at each oxygen are again somewhere near 109.5, they are probably lower than in water due to the increased repulsion from two lone pairs. Also, rather than being two Hydrogens bent in the same direction--they will tend to arrange themselves like a staircase, so that each hydrogen points away from the other. When we draw these things, the hydrogens seem far apart--but in reality they are quite close together and don't like to hang out in the same spot. These bonds are ALL free to rotate (in both water and h2o2), so when we're discussing which way is something pointing, we're talking about how most of the molecules would like to be pointing--the probability that any one molecule is in that configuration at any given point in time. As we get into double bonds (or what is called "increasing double bond character" which can be established through resonance)--we start to lose bond rotation, I can explain this--but that's a whole other topic and I'll need to draw something out, let me know if you are interested.

This leads into the reactivity argument.

The oxygen-oxygen bond is highly polarized. Because oxygen is very electronegative, it has the property of being able to stabilize negative charges very well. However, with two of them covalently bonded what you end up with is 4 electrons repelling 4 electrons which are across the bond from them. These electrons not only push at each other in free space, but they also can "talk" to each other through the bond through what are called inductive forces.

This essentially polarizes the bond, like charges repel, opposite attract.

Often when you're looking at molecules it becomes necessary to chase the charge. If you look at a carbonyl ( a C double-bond O) the oxygen is able to leech electron density from that carbon through induction and what you end up with is not this stable, chargeless molecule (that's simply how we draw it, not how we understand it). The oxygen carries a delta-negative charge (less than 1) and the carbon a delta-positive.

If say, h202 were to see such a compound the oxygen would be thermodynamically drawn to not only relieve the repulsion from the bond with its oxygen neighbor--but also to chase after anything positive, like the carbonyl carbon.

This isn't necessarily what we'd call a "high energy bond", it's more of a weak bond really. What ends up happening--contrary to what we'd usually expect (and this is what makes peroxides special) is that one of the Hydrogens is actually pushed off the end of the molecule (with h2o2 acting as a weak acid). You end up with this highly charged up negative oxygen molecule going around looking for something that can stabilize it (and do so better than a proton). This translates to just about anything in the biological world, and thus you have your method of attack.

The HOO- group will usually go after carbons, because carbon is great at stabilizing stuff (has very weird electronic properties that we don't fully understand yet), displacing any bonds that get in its way. This stuff acts as a powerful oxidizer. So much so that its been used in rocket fuels and other such applications where an oxygen rich environment is desirable.

I hope you find all of this cool. Because I do. This is happening along the chain of every molecule in existence right now. Its like all of the substituents want to get away from each other really badly.

Think of the trigonal argument. lets say we have a sphere with rods attached to it (which can somehow move freely along the sphere--but which will not ever become disconnected regardless of the force).

So at the end of three rods we place 3 objects which have very powerful, but equal, negative charges on them. These negative charges will automatically snap into place at 120 degree angles from each other (with respect to the rods connecting them). If you introduce a fourth negative charge from above--you'll see a the tripod legs flip down and the new charge will stand straight up--the bond angles will be 109.5. Let's say we take the fourth off--the model snaps right back to 120 degree angles and a planar arrangement. If we make the charges so strong that they overwhelm a humans strength to fight them, and you apply a force to one of the objects--all of the objects would spin around the sphere in unison, maintaining their distance from one another at all costs. So this same physical property we see on the macro scale is conserved on the micro scale--it's just done more weirdly, so to speak. A huge amount of this has to do with electrons ability to exist in a "cloud" or valence shell around an atom. When you start combining atoms, you start combining their clouds and some interesting properties emerge.

Have you ever wondered why benzene can be drawn as the ring structure with a circle in the middle of it? It's not because we're lazy and wanted a symbol. It's because all of those bonds are equal and consist of shared electron density throughout the ring--and it's all happening because those electrons want to spread out.

Edit: forgot to mention that for the vector drawing above--the trick is to draw each vector without lifting your pen, tail to tail. As if each vertex is you drawing a vector from (or to, depending on electronegativity) the central atom.
 
ttystikk

ttystikk

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Whew- my head is spinning. I think I'm gonna need you to draw me a picture. I think better visually, anyway.

I remember valence and electron shells from chemistry class, so that part makes perfect sense. It also makes sense that the 'hungry' O-O-H would grab onto any carbon it can find. The rest... still spinning...
 
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A quick addition:

If we made, instead of the sphere model, a model of benzene (with 6 spheres and all the requisite constiuents) and then we magically gave our electrons ability to freely interconvert throughout the ring--we'd find that they would distribute exactly equally at exactly symmetric distances from each constituent. In benzene, every single carbon is exactly the same as the next one in terms of geometry and hybridization.

This underlies one of the bigger scientific problems of our time, particle-wave duality.

You see the physical world and the atomic world follow many of the same rules--but when they do not almost every time electrons are at the interface of the disagreement. Perfectly elastic collisions and things like that only make sense on the atomic scale. Almost every weird thing that happens on this scale--happens because of electrons. Understanding them is the key to unlocking the secrets of nature from a scientific perspective.
 
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Ask and you shall receive, pic incoming.

Okay so I'll explain the thing:

The little dots in the h2o and h2o2 drawings are electrons--I circle them (and charges) out of habit.

The next thing you see is benzene. Because electrons are free to move we draw places they can go (to atoms adjacent to them). The thick black lines, in chemistry, designate resonance forms. It is important to understand that these are fake models of the molecules that do no represent their "true" form. This is uniformly the case--all resonance models are fake.

The true model comes when we take a synthesis of all the resonance forms and share the electrons in the most equal way. What we end up is the circle in the middle (or the dotted line, to denote a partial bond).

Below this I've shown you a carboxylic acid in its de-protonated (conjugate base) form. As we all know, this exists as an anion in solution, and we draw that as one oxygen double bonded and the other single bonded with a negative charge. Again the electrons move and I show that with arrows and show you the contributing resonance form.

The synthesis of these two forms yields two single bonded oxygen, both carrying equal double bond character through their partial bonds--and both carrying a delta-negative charge (which in this case is a negative 1/2 charge). I didn't write it, but in this form the carbon is also carrying a delta positive charge--carbon wants to make 4 bonds remember? But right now in the carboxylate form it only has 3.5 bonds in a manner of speaking This is again happening through inductive forces. Both of the oxygens can stbilize negative charge well. This is all a case of things progressing to their most stable natural state. To not be in this state would cost energy.

Because there is no energy input, thermodynamics says that molecules establish these equilibrium states whenever possible. High energy bonds come when you covalently bond two molecules that had to be in a thermodynamically excited stage (energy input) in order to bond. This typically means taking a molecule out of its most stable geometry (if you're to make a high energy bond). Don't confuse that to mean all reactions require that, simply unfavorable reactions require that input of energy.
 
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ttystikk

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So the fact that the carbolic acid molecule has 3.5 out of its desired 4 bonds is the reason why it's acidic, right?
 
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it's acidic because it loses that proton easily. The reason it can lose that proton so easily is that the carboxylate (the shared bond anion) is stable. This might seem sort of weird--but remember, things are progressing down this sort-of thermodynamic well. If the anionic form of an acid is very unstable, what you've got is a super weak acid (generally speaking). If the anionic form is stable, though, the acid is stronger (though many times it's still a weak acid--strong acids dissociate completely).

The polar solvent is pulling at that positive proton (with the negatively charged oxygen molecules from say, water). It turns out that, until equilibrium is reached (because we're working with a weak acid), it is thermodynamically less energetically intensive if the solvent holds on to some of the protons (and if the hydrogen atoms from the water will also stabilize the carboxylate anion).

There are these sort of opposing forces. You can think of it as solvent carrying capacity. It can only hold so many free protons, and stabilize so many anions. The rest of the acid will be protonated and in its native form (unless we start adding a base, or something).
 
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