Epoxide/Glycol Rearrangement Using HCL

Spacemonkey · Mon Feb 14, 2005 4:03 am

Does anyone have the writeup for this?

I think it was posted by Chromic or Goiterjoe but don't hold me to that

java · Consumer

Oxidation of propenylbenzenes to P2P's using Oxone
by Chromic
Oxone Technical Information
Discussion of oxone epoxidations

This method is 100% OTC. It is awesome for a first time chemist not interested in yields or time constraints, but rather in producing an active product without the purchase of suspect chemicals.

Running the reaction

Setup a 1L or 2L flask for reflux, optionally monitoring the temperature.

Add 100mmol alkene (eg 16.2g isosafrole, see note)
Add 200mL MeOH
Drop in a 2" stir-bar and start the stirrer
Add 500mL distilled H2O.
Add 200mmol KHSO5*1/2KHSO4*1/2K2SO4 (~72.7g Oxone)
Slowly add 290mmol (24.4g) NaHCO3

This will form a swirling white brew of chemicals in your flask.

Let this reaction run 5h with no external heating.

Extracting the goods

Turn off the stirrer, and let the mixture settle. The sediment will drop to the bottom. Pour off as much as possible into a beaker without getting any solids in. Suction filter the rest. The crystals will be off-white. A lot of your product will remain in the crystals. Rinse the crystals with fresh methanol to try and get as much product out as possible. The crystals should be bright white after rinsing twice.

Load into your 1 or 2L sep funnel and extract 3x100ml (or 4x60ml) with DCM.

Recover the DCM by simple distillation on a water bath.

React the oil as usual, to get ketone. If you don't know how to do the usual reaction, read the small section at the end. Purify the ketone by vacuum distillation and/or forming the bisulfite adduct, then the ketone plug into Methyl Man or Osmium's reductive amination... and away you fly!

Pool chemicals rock. The war is over.

Observations

The temperature will quickly rise to ~35(C after mixing the chemicals. The color will change from a swirling mix of white solids in a colorless and clear liquid to white solids in a light yellow liquid. As the reaction comes to completion, the temperature will drop to room temperature.

If using anethole:

The glycol oil will be a clear yellow (instead of clear and colorless, as with anethole) and no longer smell of licorice, rather like root beer... and it has maybe incorporated the smell of burnt rubber.
The ketone will have a stronger non-licorice smell-similar to, but stronger than the glycol / epoxide... less similar to root beer, and more medicinal and smelling like burnt rubber / fruity. Your phenylacetone will be a light-brown oil!

If using isosafrole:

The glycol oil will be a darker yellow (instead of clear and colorless, as with isosafrole) and will smell more like root beer after this... the same sort of burnt rubber smell is present. The yellow color won't be totally extracted by the DCM.
The ketone will have a stronger smell, losing the hints of root beer, and will have that medicinal burnt flower smell. Your phenylacetone will come out dark-yellow. In my experience, all phenylacetones have a similar smell, but each is subtly different. Some yellow color won't be able to be extracted by the DCM when extracting the ketone. The ketone is a dark red before NaOH washings which really clear up the color.

Trials

1.5g anethole (10mmol), the crude yield of ketone after steam distillation was 0.6g (3.7mmol), 37% yield.
3.0g anethole (20mmol), the crude yield of ketone was 2.2g (13.4mmol), 66% yield
14.8g anethole (100mmol), the first step crude yield was 16.4g epoxide (100mmol), 100% yield, and the crude yield after hydrolysis and washings was 12.6g ketone (77mmol), 77% yield.
24.3g isosafrole (150mmol), the first step crude yield was 22.4g epoxide (125mmol), 83% yield (sloppy technique), and the crude yield after hydrolysis, washings and vacuum distillation (~60mmHg, 190-92(C) was 13.4g ketone (75mmol), 50% yield.
32.4g isosafrole (200mmol) (300ml MeOH, 750ml H2O, 45g NaHCO3, 145.4g Oxone), from which the first step crude yield was 30.7g epoxide (171mmol), 86% yield.

Qualitative Analysis

The product from a Methyl Man or Osmium reductive amination is unmistakably active. Recrystallisation from IPA, followed by a rinse with acetone yields a bright white odorless crystal that is soluble in warm alcohol, insoluble in acetone that is not hygroscopic and completely melts below 200(C. It tests purplish-greenish black with Marquis reagent (liberating hydrogen chloride gas), and burns cleanly. 150mg will produce a smooth high complete with empathy, eye jitters, jaw clenching and pupil dilation. TLC, MS, IR or NMR has not been done for confirmation on the product.

Notes

0.1mol (100mmol) alkene is 14.8g anethole or 16.2g isosafrole. 0.1mol (100mmol) epoxide is 1.6g heavier than each alkene.
1991 ref said 1g Dupont Oxone contains 2.75mmol KHSO5, although 1985 ref said 0.2mol is 61.5g Oxone (ie 1g contains 3.25mmol KHSO5). I went with the info from the 1991 ref... who really cares anyway, as the reagent is used in excess.
The whole idea of buffering is to keep the pH only weakly acidic... note that the molecular formula for Oxone is 2KHSO5?KHSO4?K2SO4, so there's .3 mol of acidic hydrogen for .2 mol of KHSO5... which means we'd need less than .3mol of bicarbonate to leave this slightly acidic. Luckily, if too much bicarbonate is added, the pH will not exceed 8.3 due to the weak dissociation of bicarbonate ions, this is why I prefer it to sodium carbonate .
After the bicarbonate is added to the Oxone, the solution must quickly used (<10 min). It will start to liberate free oxygen and lose strength.
NaHCO3 available as baking soda. MeOH available as methyl hydrate for alcohol stove fuel. Oxone available as Oxyshock for pools (to raise active chlorine or bromine). Alkene found or derived from essential oils. Water is found distilled at a grocery store (tap water will liberate chlorine if you add Oxone, this is undesirable). DCM is available as "methylene chloride" as a paint stripper and to bond Lucite.
The reflux condenser is more of a safety / odor control device than anything else, if you don't mind the smell, an Erlenmeyer flask will work fine. You can optionally run this setup with a Claisen adapter with a thermometer to monitor the temperature.
If you don't have a large sep funnel (say if you're doing this 2-50x scale), find a large carboy or glass flask for shaking. Even HDPE plastic containers work well. Load the reaction mix and DCM, and shake it. Let it settle, pour off most of the water into another container, and then load the rest into your sep funnel. Get as much of the DCM as possible, then return the contents to the other container, load back into your shaker, and repeat. Yes, it's a bitch, but is it worth it for this purely OTC method? You be the judge.
The amount of MeOH and H2O have been successfully reduced, look at the trials section for more information. Yields may go down, there isn't enough information yet.
Good stirring is absolutely necessary, the faster the better.

Refs: J Org Chem 50, 1544-45 (1985) and J Org Chem 56, 7022-26 (1991)

The usual workup from the glycol

The more usual 65g batch is what most small-scale chemists do (after Shulgin, I suppose). In our case, we're just working with a mere 15g. Once you distilled out the DCM from the 250ml flask keep the glycol in and add:

25ml MeOH
120ml 15% H2SO4

Change the setup for reflux, and lightly reflux the mixture for 2h using a boiling hot water bath. The water bath should be kept at a light boil, and the reaction vapors will have a temp of around 65?C.

The epoxide mixture will go from a light yellowish color to more of a darker brown color.

Let it cool. Load it into a sep funnel and pour off as much of the more dense ketone as possible (both PMP2P and MDP2P are more dense than water). Now extract with 3x20ml DCM.

Wash extracts with 3x80ml 5% NaOH

For the first wash, simply rock the sep funnel back and forth. For the last two washes, shake vigorously. The sodium hydroxide washes will take away a lot of the yellowish-brown impurity color with anethole ketone, and will take away some of the reddish-brown impurity color with isosafrole ketone.

Now distill off the DCM in a water bath, or an oil bath if you're going to later vacuum or steam distill the ketone.

Notes

1kg of 15% H2SO4 is made from 150g H2SO4 and 850g H2O
1kg of 5% NaOH is made from 50g NaOH and 950g H2O
Stirring is not absolutely necessary, but beneficial. The reflux provides sufficient agitation if you don't own a hotplate/stirrer.
H2SO4 available as a high-strength drain opener (hardware store). NaOH is available as lye (soap shop, hardware store, grocery store). Info on finding DCM, water & MeOH is as above.

Preparation of Anethole

206.5g star anise oil fractionally distilled to 191.0g at 145-60(C at ~60mmHg
Distilled again, now 178.5g at 145-48(C under ~60mmHg

Preparation of Isosafrole

250ml clear yellow sassafras oil is (optionally) fractionally distilled at 145-50?C under ~60mmHg to clear colorless safrole.
Vacuum refluxed in a 2L flask (w/no stirring, no boiling stones) with 1.5wt% ground KOH flakes a la Osmium for 6 hours, the mix turns black
Distilled and tossed first 15ml back with unprocessed sassafras, collected over 200ml clear colorless isosafrole at 160-62(C under ~60mmHg.
Checked isosafrole by bringing to a reflux at atmospheric pressure and saw that the isosafrole boiled at 254(C. Successful conversion!

Thanks

Thanks go out to Psychokitty for discovering the awesome 1991 ref which lead me to the almost as awesome 1985 ref on which this method is based. Props go out to improv chem (thank you so much for your experimentation), as well as to Osmium and Rhodium for letting me know how to figure out if I really had the goods amongst my doubts. Thanx also go out to Bright Star, Methyl Man, Ezekill, Eleusis and Shulgin for raising my awareness and inspiration.

Addendum by Chromic regarding asarone

100 mmol asarone, 200mL MeOH, 500ml water, 24.4g NaHCO3, 72.7g Oxone. Stirred 5hrs, extracted with DCM, yield 89 mmol of crude asarone epoxide. A small amount was saved and the NMR spectra came back same as a good sample of anethole epoxide (with the exception of two additional methoxys).

15% H2SO4 rearrangement was attempted and it destroyed the molecule turning it into a crap that did form the bisulfite adduct. So, we just need to find another way to turn the epoxide to the ketone, Like LiI in ethyl acetate.

Btw, in my experience, crude anethole epoxide has been a clear yellow oil (smells nothing like licorice), asarone epoxide has been a light brown very viscous liquid (smells something like asarone, but quite different).

Addendum by Psychokitty

Now, lately SWIM has applied your methodology along with a few tricks of SWIM's own. Here are several suggestions (some tried, some not):

Filtering the aqueous Oxone solution (prepared according to your specifications)--both diligently and patiently--in order to remove the clarifier (which is a white soot) so that one can obtain a clear colorless Oxone solution.

Not adding the buffer (i.e., the sodium bicarbonate) ensures that the solution remains acidic throughout. Using methanol as the solvent, this does, according to SWIM, yield the diol instead of the epoxide, just as it does in the original biphasic reaction WITHOUT the methanol. Crude yield was somewhere above 90% and in reference to previous performic reactions, smelled and looked (somewhat reddish, viscous) like the real McCoy (according to SWIM).

Several samples of the post-oxidation filtered mass revealed a considerable amount of trapped expoxide (yellowish tint). Decided to solve the problem by determining what EXACTLY the mass was soluble in. Insoluble in the following moderately dilute solutions: sodium hydroxide, sodium carbonate, sodium bisulfite. Moderately soluble in an aqueous acetic acid solution. VERY soluble (completely) in a moderately dilute HCl solution (so was the clarifier, according to further--albeit dubious--tests). Didn't try using sulfuric acid. Stupid. This will have to wait.

I believe the methanol is what contributes to the formation of the slurry. It probably makes the salt mixture insoluble. If at the end of the reaction the methanol were distilled out, the solution might clear up a bit (if not altogether entirely) thus making the final extraction much easier (no filtration, that is).

First trial with this method SWIM accidently used 1-alkene which SWIM thought had been isomerized successfully. It hadn't. After reaction was done, practically 95% of the 1-alkene was recovered unharmed. The other 5% was no doubt lost through mechanical manipulation. This reaction is VERY specific to 2-alkenes and DOESN'T seem to promote by-product formation. VERY clean.

It is SWIM's opinion that the increase in temperature from 23?C to that of 36?C or above is not caused by the reaction of Oxone with the 2-alkene but through its reaction with the methanol. The resulting mild exothermic reaction thus promotes the formation of the epoxide or diol through reaction of the 2-alkene with the excess Oxone.

Old paper detailing the oxidation of many substances using Oxone hints strongly that ethanol can be used in place of methanol as the solvent in this reaction. Use of isopropanol is also possible. All solvents seem to react to some degree with the Oxone in solution.

According to the 1991 ref, buffering the Oxone solution before epoxidation ensures that by the end of the reaction, there is NO more oxidant left. The Oxone is therefore simultaneously decomposed by both the 2-alkene and the buffered solution. In contrast, the acidic solution remains quite stable with respect to any Oxone not used up in the 2-alkene hydroxylation.

Isomerization of DISTILLED 1-alkene with 1% KOH CAN be done, according to SWIM with >90% yields in under thirty minutes @ 243?C.

Experimental: Dissolve using heat and good stirring 1 gram of KOH in ethanol of methanol. Once dissolved, add 100 grams of DISTILLED 1-alkene to mixture and increase heat to distill off the alcohol, which can be reused. Place thermometer in flask and continue to heat and stir until temperature reaches 243?C (it will hit 232?C first, linger awhile, but will soon ascend). Hold for 5 minutes, the turn off heat and let cool. Next, vacuum distill to get desired product.

If dirty 1-alkene is used, considerable tar will form, covering up the KOH (making it inactive). Also, the stirring will be slowed immensely. Up to 500g of dirty 1-alkene was used. Stirrer stopped at one point but continued heating and refluxing ensured relatively complete conversion into the 2-alkene. For odor control, a dampened paper towel was lightly stuffed into the opening of the flask. Keep in mind that the cis-isomer of the alkene in question boils at 245?C at normal pressure. The trans boils at 250?C or so.

Sodium Bisulfite could destroy any excess oxidant, but there probably isn't any left over in the methanol solvent reaction because of the methanol. Anyway, in a dilute acidic solution of dichromate, the bisulfite ion is stable and reduces the oxidant. BUUUUT, in HIGHLY concentrate acidic solution, the dichromate is still reduced but a considerable amount of SO2 is evolved from the solution. So the question is, could one reduce the excess Oxone using bisulfite at a pH of 1.3 or so?

A preliminary test using the buffered epoxidation reaction, followed by hydrolysis using 15% H2SO4 yielded a mixture of products: First fraction under vac distillation was the epoxide (a light-light [lighter than the ketone] fluid oil that is almost indistiguishable from 2-alkene that does not freeze even at 0?C); second fraction, about 8?C higher than the epoxide was the ketone at the CORRECT temp (all characteristics were on the mark); last fraction was the diol @ about 10-15?C above the ketone temp (standard characteristics for those in the know). Hydrolysis of the epoxide will most certainly have to be done for longer periods of time to ensure complete conversion of the epoxide to the diol to the ketone. Crude yield was about 85% due to mechanical losses.

According to the British Patent reference detailing the performic synthesis of MVK (MethylVanillylKetone) as detailed under the "Musings on the synthesis of safrole from eugenol" heading (or whatever it's called) on Rhodium's page, the diol of isoeugenol is dehydrated using a biphasic mixture of 10% H2SO4 and toluene for every 8.1 grams of starting isoeugenol used in the reaction. According to the patent, "MVK was the first and only product isolated". My guess is that any left over by-product (such as unreacted 2-alkene) is what causes the lower yields of product and the concommitant formation of some tar during the dehydration step. Possibly the use of a biphasic toluene/dilute H2SO4 solution stirred for 6 hours is the solution to this problem.

Suggestion for experimental purposes a modification to the Oxone reaction as hinted in the above Brittish Patent reference wherein they detail a "through process" of acetylating isoeugenol to form acetyl isoeugenol, which is then epoxidized using a buffered (sodium acetate) peracetic acid solution, which is then neutralized with sodium bisulfite, which is then mixed with biphasic toluene/dilute H2SO4 and reacted to get in one pot MVK "as the first and only product":

Add all the reactants together as per your method sans the bicarbonate.

At the end of 5 hours, determine if the oxidant is spent due to the presence of methanol. If not able to due this, add the appropriate amount of sodium bisulfite in order to neutralize any excess Oxone. Keep in mind that the pH might be too acid. Determine a way to work this out. (Maybe use sodium sulfite found at the pool shop instead of bisulfite? But I think it forms a basic reaction with water, whereas bilsulfite forms an acid reaction.)

Dehydrate using any one of several ways available. If the solution was buffered, and all the acid was neutralized to completion, there will be no Oxone, but plenty of Potassium sulfate, which is not very soluble in water. Trying to make a voluminous acidic solution out of this one for the purpose of dehydration is going to be difficult.

Partial neutralization of the mixture, if done right, would leave an aqueous solution of potassium bisulfate. This has been shown to work well at dehydrating alcohols in aqeous mixtures. One could go with the diol reaction, neutralize the oxidant, buffer till bisulfate formation is complete (may already be significantly so), dehydrate with the methanol possibly distilling out (so as to avoid forming a methanol ether instead of the ketone--I read about this in a somewhat recent paper studying this reaction). And then either extract the solution with solvent or add water and steam distill.

Or, neutralize oxidant, distill our methanol and then concentrate aqueous solution and then find a way to change the solution to 10-15% H2SO4 while of course considering the potassium bisulfate and sulfate factors. Then react as per usual using just the acid solution, or with methanol, ethanol, or toluene added.

You can even go all out and start with distilled 1-alkene, isomerize as detailed above, and then add the whole sheebag directly to the Oxone mixture and epoxidize right off the bat. The KOH is in such a small amount, it probably won't make that much of a difference. If worried, however, just neutralize it with sulfuric acid or possible even better, ACETIC acid to form sodium acetate, which can act as a buffer.

Guest · Mon Feb 14, 2005 6:32 am

That's a very good (and related) writeup but I'm looking for where someone used HCL solution rather than H2SO4 to rearrange the glycol to the ketone.

I should have been more specific.
Thanks though.

Guest · Tue Feb 15, 2005 8:52 am

Yep. I've got this. Having problems registering though. When sorted, will post.

ApprenticeCook · DILLIGAF

This was a few posts at the hive, i have one by Octocambrium (?) using HCl to make mdp2p from glycol....

-------------------------------------------------------------------------

Step 3 HCl hydrolysis:
Thanks to Chromic I have never needed to do a sulfuric acid hydrolysis. HCl is really golden. In a 2L flask, you will have to do 2 hydrolysis by splitting the glycol in 2.

You need:
435 grams glycol
540 ml MeOH
900 ml water
900 ml muriatic acid

So 270 ml MeOH and 450 ml water are combined and warmed to about 60 degrees. The glycol is added(217.5 grams) followed by 450 ml muriatic acid. Upon acid addition the solution will turn a little pink/orange.

The solution is refluxed for 2.5 hours at about 80 degrees celcius. It will start to change color maybe 15 minutes after acid addition. You will see oil starting to stream on the top as it is stirring. One hour in, you will definitely see globules of oil floating around and the solution is more brown by now.
After 2.5 hours, cool down to room temp using a water bath to speed things up a bit. Place in sep funnel and sep off bottom layer. This is your oil, its dark red/black. The top layer is orange. Add a litle and extract the top layer again. 2 times 100 ml dcm is more then plenty I believe.
This step is repeated twice if you dont have anything bigger then a 2L flask.
Take your dcm/oil( combine both hydrolysis then wash) layer and wash it a couple of times with 5%NaOH. Be patient and make sure all the dcm is out. This can take multiple sepp off/wait cycles. But if you want to increase your yield do so. Then wash with fresh water, followed by brine. You can then dry it even more with epsom salts if you want.
Distill dcm. Start vacuum and distill off your ketone.

-------------------------------------------------------------------------

There are also pictures of what it looks like in each step from iso --> ketone, very nice writeup so i might find a way to get it uploaded someplace with the pictures and all.....

-AC

Guest · Wed Feb 16, 2005 6:25 am

I saved some of this thread:

*****************************
I saw this one too...

I stumbled across that article as well, but have been too busy to think about it much or post it. However, since it's here... You've left out the mass-yeild for each of those acid concentrations. Let me add that here:

Acid Product Mass (g)

2M HCl 1.07
4M HCl 1.16
6M HCl 1.13
2M HBr 0.90
4M HBr 1.00
6M HBr 1.09
2M HI 1.06
4M HI 0.77
6M HI 0.66
2M H2SO4 1.06
4M H2SO4 1.08
6M H2SO4 0.83
2M H3PO4 0.05
4M H3PO4 0.41
6M H3PO4 1.08

Now, looking at that (and ignoring differences in the molar masses of products, as in all cases the major product is pinacolone) it seems that 4M HCl gives the highest conversion and is also one of the most selective for the ketone.
One thing with this, however, is that HX can give rise to an addition product, which could decrease yeilds (of course, for HCl, this wasn't seen until reaching 6M concentration...). Another thing, if you have epoxide in the mix, would it react with the HX and give the halohydrin? And if it did, would the halohydrin be rearranged under the acid conditions?

Guest · Wed Feb 16, 2005 6:28 am

And from Chromic:

*************************************

HCl is so good it's GOLDEN!
(Rated as: excellent)

V_V, you're right on the money. Thank you! *hugs*

This ketone of a friend's is good, infact, great! It turned to slush in about 1-2 minutes in the freshly made bisulfite solution (normally this can take 5-60 minutes)

May I make a suggestion to any other bee to try using a 15% HCl rearrangement? Write-up is as follows (attentive bees will notice this is actually 5M HCl):

From the extracts from a peracid rxn containing .3mol isosaffy (48.6g), the glycol is added to: 75mL MeOH, 125ml H2O then 125ml 31.25% HCl. The mixture is refluxed 2.5 hours, the oil drained from the bottom of a sep funnel and further extracted 3x60ml DCM. The ketone distilled and at least an 80% yield can be had...

I'm expecting this yield to be closer to 85% if this guy had a better lab. This really is phenomenal if it's as good as it appears to me. I always heard of 60% yields with the peracetic/performic (likely because of the losses in the acid-catalyzed rearrangement), and I knew it's possible to hit 70% with a proper vacuum distillation... so I wouldn't be surprised if one can hit 85% of theory using this HCl rearrangement. It's almost as great as Ritter's work on the tosic method, and certainly a lot more OTC.

Spacemonkey · Wed Feb 16, 2005 8:20 am

Thanks a bunch everyone!
That's far more than I was hoping for.

[rated as: insignificant] Razz

placebo · Wed Feb 16, 2005 6:00 pm

edited from Chromic's original post on the subject.... (thats all I saved)

15% HCl rearrangement
The extracts from a peracid rxn containing 50gm isosafrole, the glycol is added to:
75mL MeOH,
125ml H2O then
125ml 31.25% HCl.
The mixture is refluxed 2.5 hours, the oil drained from the bottom of a sep funnel and further extracted 3x60ml DCM.
The ketone distilled and at least an 80% yield can be had...

All I can add is that it works, and acid amount can be halved and hence, time doubled for upscaled rxns. It works fine.

Guest · Wed Feb 16, 2005 6:09 pm

I tell a lie, here is the entire original post...

Chemistry Discourse Thread:

Subject: Rearrangement with other acids

Chromic
(Synaptic Self-Mutilator)
12-11-03 10:52
No 476034
Rearrangement with other acids
(Rated as: good idea!) Bookmark Reply

I ran out of sulfuric, went to my favorite little hardware store... tried to find some sulfuric acid on the shelf, what do you know. It's gone. They no longer stock it, but I've got a bit of glycol that needs turning into a ketone.

So I go to the library to ask the literature a question, I find that in Tetrahedron Letters 43 (2002) 9307-9309, they used a variety of acids at 2M, 4M and 6M on pinacol (unfortunately!). They used HCl, HBr, HI, H2SO4, H3PO4. Great... I've got lots of hydrochloric acid.

Acid 2M 4M 6M
HCl 100:33:10:0:0:0 100:14:0:0:0:0 100:26:0:8:7:0
HBr 100:25:7:0:0:0 100:18:2:0:0:0 100:16:2:2:0:0
HI 100:16:5:0:0:0 100:2:0:0:0:0 100:0:0:0:0:10
H2SO4 100:18:4:0:0:0 100:15:1:0:0:0 100:10:0:0:0:0
H3PO4 100:25:15:0:0:0 100:31:10:0:0:0 100:16:5:0:0:0

"Product ratio represents the relative amounts of pinacolone (1), 2,3-dimethyl-1,3-butadiene (2), and 2,3-dimethyl-3-buten-2-ol (3), 1-halo-2,3-dimethyl-2-butene (4), 3-halo-2,3-dimethyl-1-butene (5), 2,3-dimethyl-1-butene (6)."

This means that the yields for hydrochloric acid are not quite as good, right?

The 6M case for HCl really confuses me! it seems that 4M would work best... almost compareable with 2M of sulfuric (that's what 15% H2SO4, is right?)

So would people also recommend that one would make about ~12% HCl (to make a ~4M solution--conc HCl is what, 12M and 38%?) and go about the rearrangement the same? (ie with methanol, a la Shulgin)

Does anyone have experience using another acid besides H2SO4 while making MDP2P? How were the yields?

Ziqquratu
(Newbee)
12-12-03 06:44
No 476232
I saw this one too... Bookmark Reply

I stumbled across that article as well, but have been too busy to think about it much or post it. However, since it's here... You've left out the mass-yeild for each of those acid concentrations. Let me add that here:

Acid Product Mass (g)
2M HCl 1.07
4M HCl 1.16
6M HCl 1.13
2M HBr 0.90
4M HBr 1.00
6M HBr 1.09
2M HI 1.06
4M HI 0.77
6M HI 0.66
2M H2SO4 1.06
4M H2SO4 1.08
6M H2SO4 0.83
2M H3PO4 0.05
4M H3PO4 0.41
6M H3PO4 1.08

Now, looking at that (and ignoring differences in the molar masses of products, as in all cases the major product is pinacolone) it seems that 4M HCl gives the highest conversion and is also one of the most selective for the ketone.

One thing with this, however, is that HX can give rise to an addition product, which could decrease yeilds (of course, for HCl, this wasn't seen until reaching 6M concentration...). Another thing, if you have epoxide in the mix, would it react with the HX and give the halohydrin? And if it did, would the halohydrin be rearranged under the acid conditions?

--------------------------------------------------------------------------------
Anything in the name of procrastination...

Chromic
(Synaptic Self-Mutilator)
12-12-03 12:01
No 476289
Some results Bookmark Reply

No one's going to bite? Damn you! Ok, some preliminary results...

48.6g (.3mol) isosafrole peracetic (isosaffy is known to be 99%+, peracetic aged 95 hours before use at room temp), reaction seemed to go as usual (i.e. exothermic at 5 minutes, and tapered after 20 mins). 60.5g glycol isolated. Rearranged 2.5 hours with 5M hydrochloric (15%) instead of 15% H2SO4, using methanol. 49.1g crude ketone recovered. Distilled 41.8g of light orange-red ketone at 275-295C (most coming over around 285C, this is strange, usually see a light yellow ketone). (btw, does anyone note that this is a 78% yield?! normally the highest yield I've seen before this was 64% yield when using 15% h2so4--and keep in mind, I did not vacuum distill which would up the yield further--and that 64% I saw was using anethole not isosafrole) There was no forerun and little remained in the flask after.

Went to test with some old saturated bisulfite sol'n hanging around (still stunk like SO2 so I figure it's okay), but it came up negative (not even chicken fat formed...)

Uhoh. What is this oil? Doesn't smell like isosafrole. Smells like what I remember ketone to be. What could it be?

What should I recommend to this person to do? ... distill again? throw it out? aminate anyways?

Chromic
(Synaptic Self-Mutilator)
12-12-03 12:53
No 476298
Fractionally distilled Bookmark Reply

The oil was then fractionally distilled... kept what came across at 280-290C, most came across at 286C (80% of the oil was recovered). (about 10% was <280C, other 10% turned to crap in the flask) This is light yellow, smells like ketone, flows like ketone... I just don't get it!?! Perhaps his bisulfite has gone bad...

Vitus_Verdegast
(Hive Addict)
12-12-03 15:02
No 476315
that could very well be Bookmark Reply

Went to test with some old saturated bisulfite sol'n hanging around

Bisulfite solutions are not something you want to keep for long, as the bisulfite will oxidize to bisulfate. SWIM had this problem once too, he tried to form the addition compound with a substituted benzaldehyde using an old aqueous solution of NaHSO3 (also smelled/stank like SO2 does) but failed, so he figured the bisulfite must have been oxidized. Then freshly made NaHSO3 solution was tried, which worked without problems.

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The Other War (http://www.markfiore.com/animation/drugs.html)

Chromic
(Synaptic Self-Mutilator)
12-12-03 16:38
No 476334
HCl is so good it's GOLDEN!
(Rated as: excellent) Bookmark Reply

V_V, you're right on the money. Thank you! *hugs*

This ketone of a friend's is good, infact, great! It turned to slush in about 1-2 minutes in the freshly made bisulfite solution (normally this can take 5-60 minutes)

May I make a suggestion to any other bee to try using a 15% HCl rearrangement? Write-up is as follows (attentive bees will notice this is actually 5M HCl):

From the extracts from a peracid rxn containing .3mol isosaffy (48.6g), the glycol is added to: 75mL MeOH, 125ml H2O then 125ml 31.25% HCl. The mixture is refluxed 2.5 hours, the oil drained from the bottom of a sep funnel and further extracted 3x60ml DCM. The ketone distilled and at least an 80% yield can be had...

I'm expecting this yield to be closer to 85% if this guy had a better lab. This really is phenomenal if it's as good as it appears to me. I always heard of 60% yields with the peracetic/performic (likely because of the losses in the acid-catalyzed rearrangement), and I knew it's possible to hit 70% with a proper vacuum distillation... so I wouldn't be surprised if one can hit 85% of theory using this HCl rearrangement. It's almost as great as Ritter's work on the tosic method, and certainly a lot more OTC.

Chromic
(Synaptic Self-Mutilator)
12-12-03 16:41
No 476335
Repeated once more Bookmark Reply

This is a 14% higher yield than I've ever seen before... plus uses an easier to find, handle, and prepare acid.

Rhodium
(Chief Bee)
12-12-03 17:03
No 476342
Effect of various acids on pinacol rearrangement
(Rated as: good read) Bookmark Reply

Effect of various acids at different concentrations on the pinacol rearrangement
Monica De Lezaeta, Wajiha Sattara, Paris Svoronos, Sasan Karimi, Gopal Subramaniam
Tetrahedron Letters 43(51), 9307-9309 (2002) (https://www.rhodium.ws/pdf/pinacol.various.acids.pdf)
DOI:10.1016/S0040-4039(02)02379-1

Abstract
The formation of side products in the pinacol–pinacolone rearrangement was studied as a function of concentration and strength of various aqueous acids using 1H NMR spectroscopy. In all cases, pinacolone was the principal product and in most cases, its relative yield decreased with respect to 2,3-dimethyl-1,3-butadiene, when the acid concentration was lowered or the corresponding conjugate base was added.

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The Hive - Clandestine Chemists Without Borders

Chromic
(Synaptic Self-Mutilator)
12-13-03 03:18
No 476430
Good good Bookmark Reply

Forms the ketoxime just fine. In fact the ketoxime is white, I thought he had fucked up and it was the inorganic salt that always forms... before it's always been off-white. This is some nice ketone. I highly recommend this method to any other bee who may be reading this.

P.S. please, someone, confirm this! if this is as easy as it seems, it should go into the peracid faq ASAP.

Antibody2
(LinguisticBee)
12-13-03 14:39
No 476564
thats really cool chromic! Bookmark Reply

thats really cool chromic!

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We are all just witnesses.

Chromic
(Synaptic Self-Mutilator)
12-13-03 16:18
No 476573
Yield using the ketone Bookmark Reply

There was 17.9g of amine hydrochloride from 15.1g of ketone (this yield is before recrystallizing--btw this is 92% of theory from a Al/Hg). The yields on the ketoxime were likewise really good as well.

Somebody--anybody test this... I haven't heard of a smoother rearrangement in my life. (with exception of the tosic acid method that Ritter, Scoobie Doo and others mentioned) People using H2SO4 may just be throwing away 15% of their potential ketone (plus getting more crap from undesired side-reactions).

P.S. the yield on 50mmol of ketone was 92%. (8.8g ketoxime from 8.9g ketone)

Chromic
(Synaptic Self-Mutilator)
12-13-03 16:31
No 476574
Asarone Bookmark Reply

I wonder if this may be a decent way to TMA-2. An H2SO4 rearrangement will really chew up the asarone oxidation product (glycol, monoacetyl glycol, epoxide, whatever it is)--although it most definitely works. I wonder if this rearrangement would be more gentle and give a better yield of asarone's ketone.

Antibody2
(LinguisticBee)
12-16-03 11:50
No 477119
that would depend chromic, if the asarone... Bookmark Reply

that would depend chromic, if the asarone survived the peracetic rxn. My impression was that asarone decomposed/polymerized in the oxidation step not the hydrolysis step.

This assumption is based on some old pseudonitration experiments i did with asarone using HOAc as the solvent. The asarone became a purple ball of tar when left nitrating in HOAc overnight. I don't know for certain that it was the GAA alone that caused this or whether the NO2 played a role as well.

As well, goiterjoe did some peracetic trials on asarone with no sucess as far as i know, but again i am not sure if it was the oxidation or the hydrolysis that failed. Ask him.

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We are all just witnesses.

Chromic
(Synaptic Self-Mutilator)
12-16-03 17:50
No 477151
tma-2 Bookmark Reply

I made tma-2 with the peracetic in DCM--the problem was not the oxidation.

The problem was the H2SO4 hydrolysis. The asarone epoxide that came out of the peracetic was beautiful. The ketone was however crap, no better than 25-50% pure if I had to guess. It still made good tma-2 through your oxime reduction... I tripped my balls off and thought I was going to die.

That's why I'm wondering about the HCl hydrolysis. Does no one make ketones anymore? Come on guys! This could be a revolution for anyone using peracid techniques. (oxone, peracetic, performic)

edit: the hurry is that a lot of bees might be wasting a good part of their yields (and precious isosafrole). If this works, I'd like to see the word get out asap on rhodium's site. okay, sure, I'm impatient... btw it's good to hear that someone else will test this out as well.

hypo
(Hive Addict)
12-16-03 17:53
No 477152
hey now... Bookmark Reply

what's the hurry? i'll try this on iso-myristicin, but please
give me a few weeks.

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filter(lambda W : W not in 'ILLITERATE','BULLSHIT')

otto
(Hive Bee)
12-17-03 06:22
No 477235
hi Chromic, otto has had the same experiences. Bookmark Reply

hi Chromic,

otto has had the same experiences. the asarone epoxide has been made nicely using bleach but then h2so4 hydrolysis gave only 30% yield of the ketone after purification (chromatography).

otto

hellman
(Obsolete)
02-20-04 19:27
No 489942
kudos Bookmark Reply

This is an incredible achievement,

Is this an otc dream, this with the peracetic, performic(oxalic+glcerin), many bees fear is further reduced,

Excellent chromic, this should be written up everywhere,
This is especially handy to oz bees, that have no access to h2so4, this is a great way!!!

Well done

hm

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I went down to the depot of evolution, and ordered the man to supply me enough, to last a lifetime..

amine
(Hive Bee)
04-14-04 16:56
No 500742
Chromic is god!!! Bookmark Reply

Wow, as we speak, swim has the most beautiful ketone distilling a light green color comming over at around 147C. Swim used chromics technique and wow, it is sooooo much easier than the H2SO4 hydrolysis, the reaction looks clean throughout and you can see product formation, the syruppy glycol slowly turns into globules of a dark golden color. The rest of the solution remains orange.
Post reaction a beautiful dark golden oil falls to the bottom.

Wow....this by far is the cleanest method swim has used.
Props to chromic.

had swims vacuum adapter break Sad

but swim ghetto rigged something that works (using a 2 neck 500ml flask...) and a stopper with a hole in it.

ApprenticeCook
(Hive Bee)
04-14-04 20:22
No 500764
Re: Hellman - This is especially handy to oz... Bookmark Reply

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Hellman - This is especially handy to oz bees, that have no access to h2so4, this is a great way!!!

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Jesus could you be any more WRONG! oz bee, speaking from ACTUALLY BEING ONE access to sulphuric acid is a peice of piss.... waltz your ass to ANY (no sources from me) and say "hey can i have some car battery acid 98%?" and all they say is "OK that will be $4 a litre" fuck sake.... the bottle has written on it in big fat ass letters H2SO4 98% along with all the normal crap danger blah blah blah....

NO ACCESS my ass.... cant name a source but if you think hard enough you'll figure it out... hellman may not though..

Vitus_Verdegast
(Hive Addict)
04-14-04 21:20
No 500769
never mind hellman Bookmark Reply

He doesn't seem to know that the degree of industrialization of a country is measured in the tonnes of sulfuric acid it consumes every year.

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"It is the declared policy of the US Government to create a Drug-Free America by 1995."

Vitus_Verdegast
(Hive Addict)
04-16-04 09:00
No 500995
Preparation of 2,3-DM-4,5-MDP2P
(Rated as: excellent) Bookmark Reply

Preparation of 2,3-dimethoxy-4,5-methylenedioxyphenylacetone by buffered performic acid oxidation of isodillapiole, followed by Pinacol rearrangement of the intermediate glycol (formyl ester) using aqueous hydrochloric acid.
by Vitus Verdegast

In a 1L three-neck flask, set up with an addition funnel, was added 29.5 g (0.142 mol) isodillapiole dissolved in 55 ml dichloromethane, followed by 7.1 g (0.08 mol) sodium bicarbonate. To the addition funnel was added a solution of performic acid, which was prepared an hour before by mixing 30.6 g (0.225 mol) 25% hydrogen peroxide and 29 ml (35 g, 0.645 mol) 85% formic acid. This was added dropwise to the stirring suspension in the flask, which caused a lot of foaming due to the liberation of CO2. The addition took around 90 minutes, and the two-phase mixture was allowed to stir for an additional 16 hours. At the 3 hour point, a TLC was done on a sample (solvent: methanol, detection: iodine vapours) which showed a large spot -presumably of both the glycol and glycol formyl ester- and only a very minor spot of isodillapiole, so it is safe to say that most of the olefin was consumed at this point.

The organic layer was separated and washed twice with water. The dichloromethane was distilled off and the resulting dark-red oil was taken up in 40 ml methanol. To this was added 60 ml water, followed by 60 ml 29.5% hydrochloric acid. This mixture was refluxed for 3 hours and after letting it cool to room temperature, the dark oily precipitate was separated, and the mother liquor extracted once with 60 ml dichloromethane. The extract and the oil were pooled, washed twice with water and once with an aqueous NaHCO3 solution. The washings and the mother liquor were pooled and a small amount of oil was separated off and added to the organic solution1. The dichloromethane was distilled off, then vacuum was applied and 17 g of greenish-yellow 2,3-dimethoxy-4,5-methylenedioxyphenylacetone came over at 195°C at the fridge pump (50% overall yield)2.

1. TLC (solvent: petroleum ether, detection: iodine vapours) showed that all glycol (formyl ester) was consumed and the post-reaction extract gave a single spot of the ketone, at a somewhat lower Rf value than the former. It must be noted that both the glycol (formyl ester) and the ketone contained an impurity which did not elute with this solvent system.

2. The somewhat low yield was due to the use of an insufficient vacuum, as during the whole distillation smoke was seen entering the receiver. The column was warmed with an electric insulating mantle to prevent massive polymerisation caused by heating the oil too long. To obtain better results, the boiling point of the ketone must be kept under at least 185°C, as was observed before by Antibody2 3. A dark, viscous, sharp-smelling residue was left in the distilling flask, which solidified on cooling. The colour of the ketone went from greenish-yellow to a more golden tint after standing an hour at room temperature.

3. Post 250280 (Antibody2: "Complete synthesis of DMMDA-2 and DMMDMA-2", Methods Discourse)

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"It is the declared policy of the US Government to create a Drug-Free America by 1995."

Vitus_Verdegast
(Hive Addict)
04-16-04 09:41
No 501004
Well, Chromic, Bookmark Reply

Here is what you asked for, although the final part is probably not what you wanted .
I should have known that my good friend the fridge pump would not be able to do the job properly, but at least it is proven that it is possible to obtain a workable amount of 2,3-dimethoxy-4,5-methylenedioxyphenylacetone using a fridge pump (or an aspirator for that matter).

I'm thinking of trying your procedure again with a lower boiling ketone, like 4-methoxyphenylacetone, to get a more accurate view on the differences between using HCl and H2SO4.

While we are at it, by the way, does anyone know of some good parfumery formulas? I was thinking of utilizing these good scenting compounds (especially the latter 4-methoxy compound) in deodorant or candles maybe.

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"It is the declared policy of the US Government to create a Drug-Free America by 1995."

Vitus_Verdegast
(Hive Addict)
04-17-04 06:15
No 501111
Rf values Bookmark Reply

These are the Rf values for those who are interested:

silica gel plates, solvent methanol:
dillapiole: 0.58
isodillapiole: 0.57
isodillapiole glycol (formyl ester): 0.52 (taken during performic oxidation after 3 hours of stirring)

silica gel plates, solvent petroleum ether:
isodillapiole glycol (formyl ester): 0.07-0.15 (a streak rather than a spot, probably due to mixture of glycol and ester?)
2,3-dimethoxy-4,5-methylenedioxyphenylacetone: 0.05

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"It is the declared policy of the US Government to create a Drug-Free America by 1995."

ephemeral
(Stranger)
04-23-04 01:26
No 502263
Could advice be given on the appropriate ratio Bookmark Reply

Could advice be given on the appropriate ratio of acid to glycol for rearrangement.
The acid molar concentration is there, but swim didnt see how to extrapolate an acid/glycol ratio. Sorry if it was missed, TFSE is down right now and cant get to a library for a little while.

Thanks

hypo
(Hive Addict)
04-26-04 05:46
No 502940
no surprise: iso-myristicin works too. Bookmark Reply

but same problem as vitus: major scorching, so no difference
between HCl/H2SO4 noted. otoh needing only catalytic amounts
of H2SO4 is a huge plus on the aquisition side.

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http://www.animalyawns.com/

hypo
(Hive Addict)
04-27-04 17:13
No 503279
weirdness Bookmark Reply

the ketone crystallised overnight to give pretty yellow crystalls,
making me believe that it's of outstanding purity. but the oxime
oiled out. at least the oil is clear and not yellow like it used
to be with H2SO4-ketone. i wonder if MMDP2P needs longer for oximation?

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http://www.animalyawns.com/

Rhodium
(Chief Bee)
04-28-04 00:36
No 503308
myristicin ketone/oxime mp Bookmark Reply

I found these references for the myristicin ketone mp:

55°C (from H2O) Scandola; AANLAW; Atti Accad.Naz.Lincei Cl.Sci.Fis.Mat.Nat.Rend.; <5> 21 I; 1912; 49.
(prepared from either isomyristicin dibromide or from beta-nitro-isomyristicin)

49-50°C Takeya, Tetsuya; Okubo, Toru; Nishida, Shoichi; Tobinaga, Seisho; Chem.Pharm.Bull. 33(9), 3599-3607 (1985)
(prepared by Fe/HCl reduction of beta-nitro-isomyristicin)

The oxime is described as prisms, mp 111-112°C (from petroleum ether), referencing Scandola above.

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The Hive - Clandestine Chemists Without Borders

hypo
(Hive Addict)
04-28-04 01:04
No 503315
thank you Bookmark Reply

no mp of the ketone was taken. next time.

the oxime is starting to crystallise.

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http://www.animalyawns.com/

Aurelius
(Active Asperger Archivist)
04-29-04 17:00
No 503693
MP Bookmark Reply

Take a small amount of your oxime back to the ketone- then take the mp. And be sure to take the mp of your oxime.

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Act quickly or not at all.

hypo
(Hive Addict)
04-30-04 05:23
No 503795
??? Bookmark Reply

> And be sure to take the mp of your oxime.

crude oxime (took 3 days(!) to crystallise):
mp: about 98°C
color: white with a hint of yellow
smell: a hint of the ketone
no recrystallisation will be attempted.

> Take a small amount of your oxime back to the ketone- then take the mp.

what for? the identity is well known.

two notes:
a) H2SO4 rearrangement never gave crystalline oxime. fractionating was
never an option due to scorching.
b) only 50% (pretty exactly!) of the oxime crystallised in the above
way. the rest oiled ot as orange oil on addition of more water. but
this fraction is starting to crystallise too. so my suggestion is to
not add more water than given by sonson. the alcohol (ethanol in this
case) seems to hold the impurities better than the oxime.

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http://www.animalyawns.com/

otto
(Hive Bee)
05-02-04 06:01
No 504222
working on asarone
(Rated as: excellent) Bookmark Reply

TMP2P from asarone1

100 mL tap water, 5 g Na2CO3, 3.5 g KBr (30 mmol), 100 mL acetonitril, asarone (5 g of a 90% pure batch, from vacdest of etheral oil of calamus, 21.4 mmol), were put into a 500 mL beaker. Under magnetic stirring bleach solution was added in portions of 10 mL three times over 10 min. A TLC of the upper phase showed remaining starting material2 and more bleach was added in 1 mL portions (to a total of 36 mL, titrated to be 1.25 mmol/mL, 45 mmols, 2.1 equivalents) until the dissapearance of asarone on TLC. Stirring was continued for 25 min. Then, the upper phase was separated and the lower aqueous extracted twice with 50 mL of ethyl acetate. The combined organic phases were rotavapped and to the residue were added 30 mL of methanole and 100 mL 15% hydrochloric acid. This mixture was kept at 75°C for 90 min with stirring. After cooling down, the mixture was extracted three times with 30 mL of CHCl3. The combined extracts were rotavapped and the residue vacuum-destilled3. 2.16 g (45% molar yield) of a dark yellow oil with the typical smell of TMP2P.

This is the highest yield otto has obtained so far for this reaction. May be 90 min rearrangement time is too short and 75°C are too low a temperature. However, we clarly see that HCl is superior to H2SO4 in rearrangement also for TMP2P.

[1] according to a previous experiment (Post 427073 (otto: "the next day otto tried it.", Novel Discourse))
[2] Rf values in Post 427073 (otto: "the next day otto tried it.", Novel Discourse)
[3] during vacdest there was a lot of bumping. This could possibly be circumvented by drying the compound prior to destillation.

psychokitty
(«»)
05-02-04 10:47
No 504264
What do you think about this? Bookmark Reply

"There was no forerun and little remained in the flask after . . ."

Chromic: Do you think that then that the final undistilled ketone product from your aqueous HCl glycol dehydration is clean enough to be used directly in the next reductive amination step?

If so, this new application of HCl could allow one to go directly from the starting alkene all the way to the final amine-HCl without any need to purify the intermediates via possibly unneccessary distillation steps. Hence, in the future, crystallization of the final amine-HCl might prove to be the only real purification step necessary to get a clean product.

This is just a suggestion for those bees who have often wondered whether tedious vac distillation -- or even just simple distillation -- of intermediates would forever remain necessary.

Rhodium
(Chief Bee)
05-02-04 11:19
No 504269
This is no 'Shortcut World Championships' Bookmark Reply

I believe that it would be a *very* sucky idea to skip the ketone distillation. There are surely other carbonyl-containing products formed in the peracid oxidation/acid rearrangement procedures, and the Al/Hg will aminate any aldehyde, ketone or carboxylic acid in that mixture. I doubt that a simple recrystallization will remove all those byproducts reliably.

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The Hive - Clandestine Chemists Without Borders

psychokitty
(«»)
05-02-04 15:49
No 504313
I respect your commitment to purity but . . . Bookmark Reply

First and foremost, we are scientists here at the Hive. I'm only interested in determining the full dynamics and parameters of this popular synthesis. There is valuable scientific knowledge to be had in knowing that one COULD -- theoretically speaking -- carry this synthesis straight-through without the need for vac distillation or simple distillation along the way.

But for what it's worth, I completely agree with you that crystallization at the end would likely not be good enough to remove all of the by-products. While some may find this alarming, I would say purity of the final product for CONSUMPTION is an area of concern for the black market, fundamentally both a legal and health issue, and not one that should necessarily be limiting to the field of scientific research.

I merely intersted in proving one thing: That this synthesis can continue to provide relatively pure intermediates by changing the reaction conditions.

That's all.

Enjoy!

ApprenticeCook · DILLIGAF

YIPPEE!!!! i saw the original post in the thread by me.... haha
anyway thanks for the entire thread "guest" can you please register so you attribute a name to your posts....

-AC

placebo · Sun Feb 20, 2005 5:28 pm

It was me... placebo.
I wasnt logged in at the time but I thought it was obvious by the posts.