From: "Experimental Organic Chemistry" by Gilbert, J.C. & Martin, S.F. (2nd ed., Saunders College Publishing), p299-303 (1998)

"10.5 - Addition of Hydrobromic Acid to Alkenes

In this experiment, the ionic addition of hydrobromic acid, H-Br, to 1-hexene [we all know the substitute here!] to yield 2-bromohexane according to Markovnokov's rule is examined. This type of reaction is normally rather difficult to perform in the undergraduate laboratory for several reasons. First, common alkenes are immiscible with the concentrated aqueous hydrobromic acid, and the reaction is sluggish if the layers are not mixed efficiently. Second, H-Br is a strong acid that protonates water extensively to give the hydronium ion, H3O+, which is a weaker acid than undissociated hydrobromic acid and is unable to protonate the alkene rapidly under mild reactions conditions. Moreover, the presence of water in the reaction mixture introduces the possibility of competing acid-catalyzed addition of water to the alkene. These problems are reduced by using anhydrous hydrogen bromide, but the highly corrosive nature of this gas makes it difficult to handle and use.

A convenient solution to these experimental difficulties entails the addition of a catalytic amount of a quanternary ammonium salt such as methyltrioctylammonium Chloride, CH3(n-C8H17)3N+Cl-, also known as Aliquat 336® [soon to be at stores near you, Strike would suppose], to the heterogeneous mixture of the aqueous acid and the alkene. The tetraalkyl ammonium salt partitions between the aqueous and organic phases because of the amphoteric nature of the catalyst. By forming a complex with the H-Br, the quaternary ammonium salt extracts H-Br from the aqueous phase, transporting it into the organic phase and the presence of the alkene. The quaternary ammonium salt repartitions into the aqueous phase to complete the catalytic cycle. The transfer of the H-Br into the organic phase essentially dehydrates the acid, making it more reactive toward the alkene so that the addition becomes possible [Interesting!].

Compounds that promote the transport of reagents between immiscible layers by means of ion pairs are called phase-transfer catalysts. Their presence can have dramatic effects on the rates of bimolecular reactions between reagents contained in immiscible phases. One factor that determines the overall rate of a reaction involving phase-transfer catalysis is the efficiency of the partitioning of the reagents and reactants between the two phases. This is a function of the total surface area at the interface of the two phases. To increase this area, the reaction mixture must be vigorously agitated by stirring or shaking to promote the emulsification and the formation of tiny droplets of the imiscible layers.

EXPERIMENTAL PROCEDURE:

Addition of Hydrogen Bromide to 1-Hexene:

Apparatus: A 25mL and a 50mL round-bottom flask, separatory funnel, apparatus for heating under reflux, simple distillation, magnetic stirring and flameless heating.

Setting Up: Combine 3mL of 1-hexene, 14mL of 48% aqueous hydrobromic acid, and 1g of methyltrioctylammonium chloride in the 50mL round-bottom flask. Equip the flask with a water- cooled condensor and set up the apparatus under reflux (no drying tube is necessary.

Addition and Work-Up: With rapid stirring, heat the heterogeneous reaction mixture under gentle reflux for 2 h and then allow the mixture to cool to room temperature.

Carefully transfer the two-phase mixture to a separatory funnel, rinse the reaction flask with 15mL of petroleum ether (bp 60-70C, 760 Torr), and add the rinse to the separatory funnel. Shake the funnel thoroughly and allow the layers to separate. Verify that the lower one is the aqueous phase and remove it. Sequentially wash the organic phase with two 15mL portions of 10% sodium bicarbonate solution. Vent the funnel frequently because gas is evolved [Remember folks, this is a text written for U. of Texas students. Not the brightest in the world you know!] and excessive pressure must not develop in the funnel. Transfer the organic layer to an Erlenmeyer flask and dry it with swirling over several spatual-tips full of anhydrous sodium sulfate for at least 0.5 h. Add additional portions of anhydrous sodium sulfate if the liquid remains cloudy.

Isolation: Decant or gravity-filter the dried solution into a 25mL round-bottom flask, equip the flask for simple distillation, and distill the product."

Later in the chapter we are told that an average of 70+% 2-Bromohexane is the outcome. Man is that a quick, easy bromination. Proof positive use (finally!) of regular old 48% HBr IN WATER! This will now be the method of choice for bromination should Strike ever need it.

Labrat
Member   posted 11-30-98 09:49 AM          
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A similar method has been proposed by Everyman a long time ago. He was interested in making MDMA from eugenol and posted a phase-transfer catalysed rxn on:
1)adding HBr to the alkene and 2)demethylating the methoxy group of eugenol.
The conditions used in this reaction are thus also good for demethylating ethers. Thus, if safrole is reacted under these conditions, the methylenedioxy-bridge can be broken.

A possible way to prevent this, is by dissolving the alkene (=>safrole) in methylene chloride and use this mixture as the organic phase. Lr/

Labrat
Member   posted 11-30-98 09:49 AM          
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A similar method has been proposed by Everyman a long time ago. He was interested in making MDMA from eugenol and posted a phase-transfer catalysed rxn on:
1)adding HBr to the alkene and 2)demethylating the methoxy group of eugenol.
The conditions used in this reaction are thus also good for demethylating ethers. Thus, if safrole is reacted under these conditions, the methylenedioxy-bridge can be broken.

A possible way to prevent this, is by dissolving the alkene (=>safrole) in methylene chloride and use this mixture as the organic phase. Lr/

Rhodium
Administrator   posted 11-30-98 01:04 PM          
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I have already tried this. 10 moles of 37% HCl to one mole of safrole and 0.1 mole of Aliquat 336 refluxed for 5h gave good yields of chlorosafrole. A similar procedure using 48% HBr gave mostly tar.
 
drone 342
Member   posted 11-30-98 03:50 PM          
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Strike,
THe problem is that HBr with a PTC is an excellent way of getting rid of the methylene bridge, at which point, you got a big mess. I suspect this is why Rhodium got the results he did. I suggest:

1) Make chlorosafrole, then replace the clorine with Br- or I- with the appropriate alkali halide.

2) Looking through the exhaustive, extensive list of ref's I provided on adding acids across allylbenzene's olefinic double bond for a better method.

In truth, the whole halosafrole thing lost its appeal to me, but maybe you can still make it work.

-drone #342

drone 342
Member   posted 11-30-98 04:11 PM          
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In the list of ref's I gave, there are several examples of 48% HBr beeing used.
 
Strike
Administrator   posted 11-30-98 10:03 PM          
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These are all good points (See! Strike told told you guys that all of ya'll are smarter than Strike). Strike does not dispute that there is a possibility of breaking the ether bonds of the ring. Especially if reflux is applied. But reflux above is probably lower due to the solvent nature of the substrate (1-hexene).
Strike knows the energy of dissociation of the ether bonds, as well as that of a methoxy bond are too high for the HBr concentration at 48% without full-blown reflux. But in this system the safrole and 48% HBr will never be in direct contact because of the two phases (solvent and water. This leaves the catalyst to bring the HBr to the safrole. The more energetically favorable point of attack is the doublebond.

But you guys are right. Strike has no way of knowing for sure if the methylenedioxy ether breakage will occur in considerable numbers or very little. At two hours time it may not. Hell...Strike doesn't know.

Strike can tell you that this Spring when Strikie was getting proposals from actual contract laboratories for research-for-hire method development to test the P2Pol/H2SO4 theory, Strike also had proposals for bromination on representaive molecules (myristicin and eugenol). Strike thought it would be the bomb to try the H2SO4/KBr/DMSO proposal. And they would have had to fdo so because we were paying them to do what we asked. But every one of them (pHD chemists) thought that making an P2Pol first (via a boron method) then brominating the OH intermediate was the easier and more economical to do. And Strike asked if reflux of aq 48% in the method would break the ether bonds. They, all of them, said it would not.

Course after the disappointing P2Pol/H2SO4 fiasco, Strike never got around to funding the other stunts (It costs $1200.00 a pop to do thees things you know!). But Strike remembers their position on the ether bond breakage. Strike just wonders if there is a fine line that can be avoided in the above reaction to make it work.

Laters!

 
Rhodium
Administrator   posted 12-01-98 03:05 PM          
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But how would you make boron attach exclusivly in the 2-position? With safrole, B2H6 would only give the 3-borane, and with isosafrole a 50/50 mix of 1- and 2-borane.
 
drone 342
Member   posted 12-01-98 03:22 PM          
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I hate to bring up the ugly MDP-2-Pol specter, but it seems important. Now before, you said the problem was that this alcohol isomerized at the drop of a hat; but now you're saying that it won't in this case; how has this issue been resolved?
-drone #342

Strike
Administrator   posted 12-02-98 01:43 AM          
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Drone - The proposed method for making P2Pol using sulfuric acid was the procedure that resulted in alpha carbon migration. The boron method (sorry but Strike has already forgotten the particulars) was the one that was proposed to make straight-up beta OH. But it was never tried so I cannot say either way.
 
Rhodium
Administrator   posted 12-02-98 02:30 AM          
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Strike: You could not post their complete report on the MDP2Pol experiments, even if their main product was the 1-ol? Their results could perhaps be used for the synthesis of other MD analogs? I for one would be very interested in their procedures and yields of the alcohol.
 
Piglet
Member   posted 12-02-98 05:33 AM          
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If you are using B2H6, you may as well procede from there to the amine. The method is detailed in 'psychedelic chemistry'.
If simple procedures are the name of the game, what about halohydrin formation? Chlorine water followed by reflux with LiI to make P2P, As seen in 'The Complete Book of Ecstacy' (some refs in the hive as well)?
Just a thought,
Piglet 

Rhodium
Administrator   posted 12-02-98 07:26 AM          
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But doesn't the problem lie in that B2H6 adds all over the place, and not just in the 2-position?
As far as I know, there isn't any method in TCBOE which goes through a halohydrin intermediate. There is one method where the vicinal dichloro/dibromo compound is prepared, which is refluxed in KOH to yield the P2P. Could you clarify?

Thanks for the pointer to Psychedelic Chemistry, I had completely missed that method of amphetamine preparation - why haven't anyone mentioned that one before?

Piglet
Member   posted 12-02-98 08:31 AM          
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No, the borane method is a general addition method which, as far as I know, is specific. As for why it hasn't recieved much attention, well, it's hardly OTC stuff, is it? If you can get hold of all those reagents (and handle them safely), you may as well use #3 & a hydride reduction!
TCBOE uses the dihalide but also points out that if water is present the halohydrin will be formed, which can be rearranged similarly. I forget the thread, but I did post the patent number and drone gave some pointers as well.

Rhodium
Administrator   posted 12-02-98 01:52 PM          
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Carey, Organic Chemistry, p 232:
"There is a pronounced tendency for boron to become bonded to the less substituted carbon of the double bond. Thus, the hydrogen atom of diborane add to C-2 of 1-decene, and boron to C-1. This is believed to be mainly a steric effect, but the regioselectivity of addition corresponds to Markovnikov's rule in the sense that hydrogen is the negatively polarized atom in the B-H bond, and the boron the positively polarized one. [...] The net result is the conversion of an alkene to an alcohol with a regioselectivity opposite to that obtained by acid-catalyzed hydration."

Norman, Principles of Organic Synthesis, p 484:

"The boron atom adds predominanly to the less substituted carbon atom [...]. For example, the preference for attack by boron at the two unsaturated carbon atoms of 1-butene is

[1-position - 94%] - [2-position 6%]

With 1,2-disubstituted alkenes, the selectivity is less marked, e.g. with 4,4-dimethyl-2-pentene

[2-position - 58%] - [3-position - 42%]"

So - with safrole, the diborane will add to the wrong carbon, and with isosafrole, half of the diborane will add to the 2-position, and half to the 3-position, if the benzylic carbon isn't too sterically hindered for that to happen, that is. Do you have any practical examples where a propenylbenzene preferably reacts with diborane in the 2-position? If so, we have a one-pot high-yield non-toxic version of Strike's #2, if the hydroboration is directly followed by chromate oxidation, I have a ref for that kind of conversion here somewhere, but I never thought it could be used, because diborane wouldn't add selectively to the 2-position.

#3 Is the Wacker oxidation of safrole, how would that combine with a hydride reduction?

But if a propenylbenzene halohydrin can be catalytically rearranged to a phenylacetone, that means that propiophenone can be transformed into P2P in three easy steps using ONLY OTC reagents!

1) Propiophenone ($50/kg) is selectively chlorinated in the 2-position by sodium hypochlorite (Chlorox).
2) The alpha-halo ketone is reduced to the halohydrin by Al(IPrO)3 (from Al/Hg in anhydrous IPrOH) with the Meerwein-Verley-Pondorff procedure.
3) The halohydrin is rearranged to P2P.

 
drone 342
Member   posted 12-02-98 04:22 PM          
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Strike,
I know the problem was migration; what I was asking was why you expect it to occur with the sulfuric acid method, but not with boron method. I'm not saying you're wrong at all, just asking "why". I thought the problem was that the alcohol was inherently unstable, but I could be wrong. I want to be wrong.

-drone #342

Strike
Administrator   posted 12-02-98 11:40 PM          
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Who knows why all these things add as they do? Strike doesn't. Why does a high concentration of HBr give beta addition, but a high concentration of H2SO4 gives alpha addition?
Strike doesn't know. As all of ya'll know, Strike is not a trained chemist and has just learned as time has gone by. All Strike does is look for methods that accomplish similar goals on similar molecules. Strike then applies them. If they work...great. If they don't...Strike usually won't tell any of you about it

Strike really does leave it up to you guys to ponder the 'whys' of it all. As far as whether the boron method would be migration free Strike does not know. It seemed to be the favored proceedure of choice with the established chemists, but without any trials Strike does not know at all. It may very well migrate on our favorite substrates.

Sincerely,

Strike

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drone 342
Member   posted 12-03-98 01:15 AM          
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Strike,
I don't mean to harp on you at all, its just that the explainaition behind why the H2SO4 reaction didn't work for anyone but you and I never sat with me right. I've still not been able to buy it completely, and that was my point. That methylendioxy ring isn't gonna be that electron-withdrawing that it should cause that hoydroxyl to migrate by itself -- especially when you consider the exhaustive series of examples of successfull additions acors that double bond that don't result in migration.

I tells ya, somethin' smells fishy, and I don't buys it!

However, so as to not pull the entire Hive into a tailspin of tedious discussion of this controversial reaction, I suggest "we take this outside". If you could, please send me any relevant data you may have on this. Like its been said a million times before, this is one of those reactions that look so good, make so much sense, and would be so convenient, that its a shame that it hasn't been investigated even more. Please e-mail me at drone342@hotmail.com at your discretion.

Thanks,

drone #342

Piglet
Member   posted 12-03-98 04:24 AM          
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I'm sure I remember PC giving a 70 something % yield of amine in 1-pot WITH a proper reference. (Though I admit it is some time since I read that book, but I'm almost sure).
My example wasn't 1-pot, It's just the BEST way of doing it in my opinion. If you can get all the solvents/reagnets that is.

If the fact it's 1-pot is all that matters to you, surely Drone's photochemical stuff is what you should research. Of course, you need some pretty exotic (for me) reagents.

drone 342
Member   posted 12-30-98 12:54 PM          
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Is this method abandoned? Is anyone interested anymore in making bromosafrole? Like I said, I have scores and scores of examples of isopropyl bromides being made from allyls, with enough variety in conditions employed to keep one busy for days reading it all.
 
rev drone
Member   posted 01-14-99 09:05 AM          
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I think we definately should talk about improvements to step 2 in this procedure -- the base-catalyzed substitution-elimination.
This is a classic reaction, and numerous alalogous reactions are well-studied from a kinetic perspective, though this one not entirely.

Basicly, there are four ways to make thi s reaction go faster/nicer:

1) Use a better leaving group (this idea was previously discussed a little in a related girgnard thread)

2) Use a stronger base as a catalyst

3) Get things hotter, so as to enable more molecules to overcome the kinetic barier of this reaction (this is the method for this reaction described in the literature, where its heated in a tube at some ungodly temperature. No thanks!)

4) Use a catalyst to effectively lower the kinetic barrier (my PTC idea is an example of this. Still, there are indications that this method alone still only helps so much.)

So, let's get crackin'. This halogenation/substitution-elimination method has the prospect of being such an easy method, if we only could figure out the finer details. In theory, it should be as easy as could be hoped for.

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-the good reverend drone

ChemHack
Member   posted 01-14-99 08:06 PM          
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Rhodium: You report that 48% HBr gives tar when refluxed with Safrole and PTC. Did you ever notice how those old refs, the Polish guys from 1961 and Carter and others from the 30's and 40's did the rxn in ice or at 0C ?
What I'm getting at is maybe this thing would work with PTC if instead of refluxing, the mixture was cooled? Perhaps there would be enough energy to add the HBr to the beta without smashing the MD bridge?

Rhodium
Administrator   posted 01-15-99 04:29 PM          
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I just noticed how nice HCl added to safrole under reflux conditions with Aliquat 336 (15 x molar excess, with only 5 x, the conversion was incomplete), and how un-nice HBr gave a tar, using a third of the amount of HBr compared to HCl (only a 5 x molar excess).
No attempts was done to improve the yields using HBr.

DoctorTom
Member   posted 01-24-99 07:17 AM          
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Dear fellow lit researching beez
Dr.Tom c/o Atlas needs a detailes "Theoretical;(), due dilligence
Supply list to produce non DEA CI controlled
analogues from the mystyricin
natural based oil from nature.

It is my understanding from injesting the material in Stike Back Book I, that this natural compound is very active and has nice color as well.

We are always looking to test and develop natural analogues to the DEA/FDA expensive and thus harmful to the public at large synthetic DEA Scedule CI-CIII drogus.

I realize that your used to double speak how ever am used to following standard General OrGII and biochemistry college standard proccedures but I Know that your and your followers are experts at removing the excess steps demanded by FDA/CDC and other tax expending agencies.

Wihtout going off on colateral extraneous yet thotful issue that face all of us please list:

A complete synthesis that does not have the cleaning steps that remove the natual active/inactive properties and contaminents but uses scientific method and appropriate apparatus and modern technique.

I Thomas A. Oth swear that I will take my own personal responsibility to protect other american as well as people of all americas, and all other peacefull nonjudgemental indians types.

I have a schedule I chemical account at Sigma. I do not sell to John Q Public.

I do pure science guy type private research that in turn help the public to get of dangerous ill health effect producing and over priced Pharmacueticvals that are sold by and through the various channels of Pact USgovernment CDC/DOD/FDA/DEA ect..etal included.

In case of paranoia or fear of legal recourse
I Thomas A. Oth, release the hive and all members for any liability legal and or other act that would be misconstrued by overzealous chriastian right or left god fearing hypoctite officers,agents and police state or federal due to contradictory policies inacted by inept degreless double speak politicals that do nothing but cause harm to me,my research and the publics interest and saftey.

I do not excuse them for political team type or knee jerk behavior as I you do not either.

I await your response,

Keep up the geurilla marketing project and the drug war will end sooner

Dr.Tom

 
rev drone
Member   posted 01-24-99 10:17 PM          
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Tom,
Your post is not pertinant to the discussion here, not to mention that its hardly legible to begin with.

quote:
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I have a schedule I chemical account at Sigma. I do not sell to John Q Public.
I do pure science guy type private research that in turn help the public to get of dangerous ill health effect producing and over priced Pharmacueticvals that are sold by and through the various channels of Pact USgovernment CDC/DOD/FDA/DEA ect..etal included.

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I really don't believe you. "Pure science guy typre research"? No, you don't.

But let's get to the matter at hand. You want us to provide your company with a synthetic procedure for a series of non-scheduled phenthylamines based on asarone, free of charge? Let's look into why that probobly won't happen:

1)This is the serious chemists only board, and you're chemistry is not serious.

2)The CSA Act made these drugs and their analogs illegal. Hence, there really aren't any analogs that could be made that would be legal.

3)This chemistry has been covered thoroughly, and if your a real science type reaserch guy, you'd know this.

4)I for one am paid when I do consulting, especially if its for a for-profit commerical endeavor. If you're making money off it, you'd better expect to pay whoever is kind enough here to help your unlearned self out.

5)Since what you're making is illegal, helping you to do this would be conspiracy. While I have no moral qualms in this matter, you do not appear to me someone I can trust with not getting in trouble (actually, you look like trouble from the beginning)

6)You're wasting a lot of space all over The Hive, posting nothing of any value. This personally upsets me.

7)You're off-topic here.

8)Your request was gibberish, and I can only really speculate as to what you were asking.

9)Your egotism is too much to put up with.

10)There are many more important things being done here than to stop everything and volunteer to help you in a quasi-legal commercial scheme.

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-the good reverend drone

Optimus Prime
Member   posted 04-17-99 09:59 PM          
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Uhh... OP humbly offers the question pertaining to the use of HBr... If used as a gas I was under the impression that you couldnt over do it... It will deprotect yet wont break peptide bonds... and NaBr I would imagine to be easier to get...
OP