7/16/2007

You're Not That Good an Isomerizer, Charlie Brown

Not to tread on Milkshake's territory, which he rules over with the iron fist so becoming of a former citizen of the Soviet bloc, but I feel it necessary to post a lil' addendum on acetylene zippers- namely, when they don't work. Conjugated alkynes don't readily undergo acetylene zipper reactions, most likely due to, uh, conjugation. I tried it with a few different aromatics and couldn't get any to work right.


I did find one example of an aromatic alkyne zipper reaction, but yields weren't great. I'm sure it was a huge pain to purify too.


So, take of it what you will. Comments? Criticism? Experience? Leave 'em- I'm open for suggestions.

19 comments:

Ψ*Ψ said...

I wonder if Milkshake has anything to say to this.

Kyle Finchsigmate said...

WTF is up with this popup that keeps telling me you need to fix your peekabo hack?

Excimer said...

fixed. sorry, that was annoying. i didn't see i cause i had my popup blocker on.

milkshake said...

Comrades,

KAPA zipper reaction needs allene formation. Our Central Milkshake Committee (=CMC) has not considered such a regrettable complication, but it is now quite predictable that the conjugated allene should perversely like to collapse back to the conjugated alkyne. Maybe the phenolate example worked only because extremely forcing conditions were used (65C, 20 hours as opposed to 25C, 3 min normally used) and the phenolate had a weaker conjugation and there was some charge repulsion effect. But 41% yield for a migration through 18 bonds is rather encouraging and the "Hero of Socialist Labour" award should be given to the comrades who could isolate anything from such mixture. (The others are to be sent for lumber camp re-eduction in the northerwestern provinces)

ArCHOH-C{triplebond}CCH2R substrates should isomerise readily so if one can live with extra benzylic OH in the product I would give it a try.

Alternatively one can try the old-fashioned Vilgerodt on your substrate (elementary sulfur + morpholine + reflux or ammonium polysulfide + water + heat in a pressure vial) if you can live with getting a thioamide instead of alkyne.

Also, Schwarz reagent 1.1 equiv. in toluene (with heating) is also worth looking into, vinyl zirconiums do izomerise to the terminal vinyl. Except that the NBS workup gives vinyl bromide.

Also, if you need to migrate your C-triplebond only across 1 or 2 carbons and can have a good el-withdraving group like CN, CO2R that conjugates better than aryl, maybe a milder base like tBuOK could re-equilibrate the triple bond to a better conjugation.

Also, there is Vilgerodt alternative based on borane addition, heating the borane to something like 190C neat to bring about zipper-like izomerization, followed by oxidation with Jones reagent to get carboxylic acid. This has been used to make omega - aryl - substituted fatty acids. (I know the guy who did this work and can ask him if you want.)

taitauwai said...

Ψ*Ψ, we don't have to wonder, for 同志 Milkshake never fail to amaze us. Ya?

Excimer said...

Thanks Milkshake. You are a treasure trove of synthetic knowledge as always.

squirmy said...

if you need the terminal alkyne, i was thinking of a little modification to the approach using the schwartz reagent.

assuming the isomerization works with the conjugated system :), if you treat the terminal alkenyl zirconocene with 1 eq of MeLi, it should kick off methane and make the zirconacyclopropene (http://dx.doi.org/10.1021/ja00242a066) you should be able to treat that zirconacycle with iodine to get the alkyne.

Excimer said...

that sounds like a lot of work, but i'll check it out. This is why i love synthetic posts. brings all the people out to talk chemistry. lord knows we can't get most people to talk about materials here aside from the regulars, try as we might sometimes.

squirmy said...

well, you might even end up with the 1,2-diiodoalkene with my suggestion, but it shouldn't be too hard to eliminate. you might even be able to do the whole thing in one pot.

if you should decide to try it, i recommend using the NBS workup first to make sure the isomerization is working.

i was also thinking if you made the aryl alkyne by sonagashira (or something similar) that you could instead use a kumada coupling of TMS-protected 6-bromo-1-alkyne.

that bromo alkyne would be a few steps in itself, though. and you definitely lose the elegance by resorting to protection/deprotection. but on the plus side, it could give you a much more satisfying experience with the zipper reaction!

Excimer said...

honestly, I've pretty much given up on the zipper in lieu of another method that makes what i want a bit more easily (blah blah proprietary blah blah IP blah blah). But thanks for the advice on the Schwartz reaction- I never thought it'd be more useful than for making me and my friend reminisce in our organometallics class about Spaceballs.

Ψ*Ψ said...

Excimer: You're right, synthetic posts do seem to bring out the chemistry people. (Too bad I suck at writing them!) It would be awesome if we could drag some physicists out to talk materials & devices with us. I know they're out there...somewhere...they're just so quiet. I think Dave is the closest we have to a physicist among the regular commenters. (Ha! If I am wrong, they have to come out now and tell me so. Right?)

andreew said...

Off topic, I know. But any comments about the various ways to remove peroxides from some really really old bottles of diethyl ether? The methods I am considering now are adsorption on alumina, reduction by ferrous sulfate, and reduction with sodium wire.

Of the three, sodium wire is preferred by the lab techs, and I like it too. It's the easiest - press sodium wire into winchester, leave at least a day, decant and distill on the rotavap. My second choice is alumina, but that's quite a slow process. I'm not in favor of ferrous sulfate because it's no fun trying to extract 10 or so liters one by one in a 1 L sep funnel.

Or, should I just dispose all of them as solvent waste and buy new bottles as needed?

(Part II). Same problem for 3 * 500 mL diglyme. This one is quite expensive and I'm not keen on chucking it all.

Ashutosh said...

Milkshake, did you write a book under the pseudonym of Jerry March (which does sound like a pseudonym to me)?

milkshake said...

No, I worked for a guy who used to make some boring stuff like omega aryl fatty acids for biologists and he was an expert on chemical zippers. I never got to do it myself though.

Peroxide ether - I would add some LAH and distill from the water bath. Sodium takes some time to reflux before ether is dry - but the advantage is that you can add benzophenone indicator and if you reflux it under inert atmosphere you should be able to see the puple ketyl radical.

I used to dry diglyme by distilling if from LAH. The only thing is that LAH decompodition is close to b.p. of diglyme at atmospheric pressure so I would recommend using a vacuum distillation at something like 50 Torr, that way the distillation residue with LAH sludge does not get overheated as much so there should be lesser risk of a fire. Anyway, if you go into trouble of drying and distilling your solvents,. you should do it under dry N2 or Ar.

milkshake said...

Excimer, I don't know exactly what you are up to - but one favorite trick of people who were making these borig saturated fatty acid analogs was to link the two pieces of the molecule with thiophene (2,5-disubst) and then desulfurate the product with excess of Raney nickel. Thiophene turns neatly into -(CH2)4-

GMC2007 said...

Any chance that the intial deprotonation could take place on aromatic ring rather than at propargylic carbon? Maybe even next to triple bond (think of the 'almost allylic' orbital interactions). Measured pKa for 2-acetylenylpyridine would be interesting. Any electron withdrawing subsituents on Ar rings for reactions that didn't work? Hydroxy on aromatic ring will deprotonate and render ring CHs less prone to deprotonation.

Excimer said...

I'm willing to bet that the phenol is deprotonated first, forming some weird quinone methide-type species. I've seen a bunch of examples of zipper reactions of aliphatic alcohols, but this is the only example of a conjugated alkyne I've seen that does the zipper in any appreciable yield. I wouldn't be surprised if having the phenol there helps.

GMC2007 said...

I wasn't thinking of the deprotonated phenol as reacting. More like if if gets deprotonated, then the (hypothesised to be undesirable) deprotonation of at the ring is less likely to take place. One can draw a rough analogy (best not to take it too far) between the phenolic hydroxyl and a sacrificial anode attached to outboard motors used in salt water.

It would be interesting to know if anyoen has tried this reaction with 2,6 disubstution flanking the alkyne.

Alexey said...

I don't have any experience with this reaction, but from general conciderations I can guess...
As a side reaction one can imagine addition of an allenyl-anion to a triple bond, especially if the triple bond is still conjugated with Ar. Even if it's not the case, there is a big chance that the "crap" is formed via some kind of intermolecular reaction. From this I can guess, that if you make low concentration of the substrate (say 10(-2)M or 10(-3)M, but big excess(10 times?) of the base and, probably, even bigger excess of diamine (to ensure fast protonation of the allenyl-anion, and, therefore, to make it ready to be deprotonated again and to go further) this could decrease the rate of "polymerization" and increase the rate of the desired reaction.