Author Topic: Please criticize: route-Acetaminophen to DOB/DOC  (Read 12421 times)

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Rhodium

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The not-MDP2Pol synthesis!
« Reply #20 on: November 04, 2003, 06:25:00 PM »
J. Chem. Soc 1947, pg. 124
"The sulphonation of some derivatives of eugenol"

Treatment of eugenol with concentrated sulphuric acid at 0 C gave largely sulphonated polymers. When O-methyleugenol, however, was sulphonated by stirring with sulphuric acid at 0 C and the sulphonic acids were extracted with water, an amorphous mass was left, from which a 5% yield of the sulfone was isolated.


Wow! You are the first to find a reference which describes this non-workable preparation of Phenyl-2-propanols from oxygenated allylbenzenes...

Here is my collection of related references:

https://www.thevespiary.org/rhodium/Rhodium/pdf/mdp2pol/


ning

  • Guest
yeah, that MD ring...
« Reply #21 on: November 05, 2003, 08:22:00 AM »
just can't take much abuse, can it? Just found a bunch of kick ass papers on oxidation of alcohols to ketones.
Do you have the one where they use TCCA and acetone to make p2p?

Rhodium

  • Guest
MD
« Reply #22 on: November 05, 2003, 08:47:00 AM »
yeah, that MD ring just can't take much abuse, can it?

It's sensitive to a lot of conditions, but the aromatic ring is also very activated by having two oxygens and one alkyl chain attached to it, so a lot of things may add to the 6-position. See for example

Post 280053

(Rhodium: "Why the Ritter Reaction Fails for Safrole", Chemistry Discourse)


Just found a bunch of kick ass papers on oxidation of alcohols to ketones. Do you have the one where they use TCCA and acetone to make p2p?

UTFSE on the volume/starting page/year for the article in question, and see if it has been posted before.

ning

  • Guest
seems to be not...
« Reply #23 on: November 05, 2003, 09:58:00 AM »
They do several clever things in that paper. I imagine the oxidation works by chlorination, first, then by removal of the HCl group, which would be absorbed by base, neatly removing two hydrogens, and changing a -OH to a =O. If this could work on hydroquinones....well, I get ahead of myself. Anyway, the major competing reaction that lowers yield is chlorination of the ketone. So they put the mixture in an excess of acetone, which is a ketone, so the acetone will compete for the chlorination, saving your precious material and raising yields. Pretty cool, actually.

This paper is cool because they actually do p2p-ol to p2p. No extrapolation needed.

Ning strongly suspects the pyridine could be replaced with Na2CO3 or some such thing as that.

Synthetic communications, 22(11), 1589 (1992)
The oxidation of secondary alcohols to ketones with trichloroisocyanuric acid

Gene A. Hiegel and Malekashtar Nalbandy

Dept. of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, California 92634

ABSTRACT: Secondary alcohols are rapidly oxidized to ketones by a solution of TCCA in acetone.

  Ketones are often synthesized by the oxidation of secondary alcohols. We wish to report a fast, simple procedure for the synthesis of ketones from secondary alcohols which is suitable for moderate to large scale reactions. (ning sez: huh huh huh)
   Trichloroisocyanuric acid [1] is a relatively stable and inexpensive reagent which has been used synthetically for the chlorination and oxidation of various types of compounds .(1) Secondary alcohols are rapidly converted into ketones with a solution of 1 in acetone containing pyridine.(2) The ketone products are isolated by extraction after removing the cyanuric acid [2] by filtration and replacing the acetone with ether. The yields and purities for the distilled or recrystallized products are shown in the table.

   R1                            R1
    \                             \
3   CHOH + TCCA + 3 Pyr --->   3  C=O + Cyanuric acid + 3 Pyr.HCl
    /                             /
   R2                            R2




Secondary alcohols are oxidized considerably faster than primary alcohols
with TCCA allowing selective oxidation of secondary alcohols in the presence of primary alcohols. Selectivity is shown by the oxidation of 2-ethyl-1,3-hexanediol to 2-ethyl-1-hydroxy-3-hexanone, the last entry in the table; none of the starting diol remained in the distilled product. Selectivity is also shown by a competitive experiment using 3.52 mmol 3-heptanol, 3.55 mmol 1-nonanol, 5.19 mmol pyridine, and 1.66 mmol TCCA. Analysis by GC after a 4-minute reaction time showed that only 2% of the 3-heptanol remained compared to 88% of the 1-nonanol.
   During the oxidation of secondary alcohols, HCl is formed, and HCl reacts with TCCA to give chlorine(3). This does not inhibit the oxidation, but since some of the chlorine escapes from the reaction mixture, the amount of oxidizing agent required to carry a reaction to completion becomes less clear. The addition of a slight excess of pyridine minimizes the formation of chlorine.
   It has been reported that TCCA will chlorinate ketones (1,5), but this unwanted side reaction can be reduced by several methods. The use of acetone as the reaction solvent limits the amount of chlorination of the ketone product.(6) The oxidation also proceeds well in acetonitrile, but a higher ratio of chloro ketone is produced. The oxidation proceeds rapidly without pyridine, but the extent of chlorination is less when pyridine is added. This is presumably because HCl promotes equilibration between the ketone and its enol, and it is the enol which is chlorinated(5). A lower ratio of TCCA to alcohol will give less chlorination because the concentration of TCCA remaining after the oxidation is complete will be less. Quenching the reaction with sodium hydrogen sulfite, which destroys TCCA, as soon as the oxidation is complete will minimize chlorination as well. Since chloro ketones are quite reactive toward nucleophiles, they are normally converted to hydroxy ketones during the sodium hydroxide wash step in the workup and are removed at either the extraction or distillation stage.
   The low cost of TCCA, the speed of the reaction, and the ease of isolation of the products make TCCA the oxidizing agent of choice for the conversion of secondary alcohols to ketones.

Experimental:

   Oxidation of 2-Octanol to 2-Octanone:

The following procedure is typical. In a 500 ml, three-neck, RB flask were placed 7.0 g (54 mmol) 2-octanol, 6.2 ml (77mmol) pyridine, 40 ml acetone, and a stir bar. The flask was fitted with a condensor, dropping funnel, and stopper. In 50 ml acetone was dissolved 5.68 g (24.4 mmol, 73.2 meq) TCCA.(7) While stirring, the solution was added from the dropping funnel over a period of 1.5 min. The mixture was stirred for total of 20 min, then checked for the presence of TCCA using wet iodide-starch test paper. The test was negative (8), so the mixture was vacuum filtered to remove the cyanuric acid, and the filtrate concentrated using a rotary evaporator. Ether, 60 ml, was added and the solution washed with 1 N HCl (2x10 ml), 4 N NaOH (10 ml), and saturated salt solution (15 ml), dried over MgSO4, and vacuum filtered. After removal of the ether, the residue was vacuum distilled through a concentric tube column to give 5.73 g. (47.0 mmol, 83%) of 2-octanone: bp 95.0-97.0 C (42 torr)); 99% pure by GC analysis; the IR and NMR spectra agreed with spectra of the standard.
   The reaction was carried out essentially the same way on a larger scale starting with 50.3 g (386 mmol) 2-octanol, 50.0 ml (620 mmol) pyridine in 250 ml acetone and 49.6 g (213 mmol) TCCA in 400 ml acetone added over a period of  60 min with 15 min additional reaction time. Distillation of the 2-octanone gave 40.6 g (317 mmol, 83%) with a bp of 77.8-80.0 C and a purity of 95% by GC.


The Table:

Oxidation of Secondary alcohols to ketones with TCCA

Alcohol             Ketone         Yield     BP/torr  Purity
-----------------------------------------------------------
3-heptanol          3-heptanone       85%    136.2/35   99%
2-octanol           2-octanone        83%    95.0 /42   99%
3-octanol           3-octanone        81%    73.6 /26   99%
cyclohexanol        cyclohexanone     68%    58.0 /26   97%
2-me-cyclohexanol   2-me-"            77%    63.8 /24   99%
menthol             menthone          82%    108.2/35   99%
borneol             camphor           86%    mp 174.8   99%
1-Ph-ethanol        1-Ph-ethanone     90%    107.0/39   99%
Ph-2-propanol    Ph-2-propanone  85%  109.8/25   99%

2-Et-1,3-hexanediol "-1-HO-3-hexanone 72%    123.2/25   95%



Refs:

1. (a) Hiegel, et al, Synth. Comm., 1985, 15,5, 385
   (b) Back et al, Can. J. Chem., 1991, 69,9, 1482
   (c) Walters, et al, J. Org. Chem., 1991, 56, 316

2. A previous report of small scale (0.5 g or less) oxidation of several steroid and two terpene alcohols using TCCA has appeared: Mukawa, F., Nippon Kagaku Zasshi, 1957,78,450; Chem abst., 1959, 53, 5338a. This study was of limited scope and a general oxidation procedure was not developed.

3. Hiegel et al, J. Chem. Ed., 1987, 64, 2, 156

4. Stevens et al, J. Org. Chem., 1980, 45, 2030

5. (a)  Radhakrishnamurti et al, Indian J. Chem., 1985, 24A, 300;
   (b)  Vasudevan et al, ibid, 304.

6. Acetone is also chlorinated, but the chloro compounds are effectively destroyed during workup.

7. As with other strong oxidizing agents, TCCA should be added to the solvent rather than the solvent being added to TCCA otherwise a violent reaction could occur. An excess of TCCA was used because some is lost due to side reactions, and it has been reported to be about 90% reactive as determined by a thiosulfate titration of the iodine liberated on reaction of TCCA with iodide. See Eaton, Mfg. Chemist and Aerosol News, 1964, 35, 12, 45.

8. If the test had been positive, then saturated NaHSO3 solution would have been added, and the solution stirred for a few minutes and tested again. This procedure would have been repeated until the test was negative.


ning

  • Guest
Eliminating the MnO2 // bleach chemistry
« Reply #24 on: November 14, 2003, 09:50:00 AM »
Ning doesn't know if the other bees have seen these papers, but amongst the other cool bleach oxididation of alcohols to ketones papers, ning found one where they use bleach & a PTC to oxidize hydroquinone to quinone, AS WELL AS OTHER ALCOHOLS TO KETONES. In the revised synth (v.3, was it?), we are oxidizing simultaneously the hydroquinone-p2p-ol to quinone-p2p with MnO2. However, if this paper is true, then perhaps we could ditch the battery gunk from the synth altogether, and just use bleach. Ning knows that for large scale synthesis, this would be a great advantage, and also that the wacker bees who want quinone would like this much better than screwing around with the awful all-staining MnO2/C mixture in batteries. Fine. Actually, ning gets the strong impression that oxidizing aminophenols and hydroquinones is pretty similar. Only problem is, bleach seems to be verrry touchy, with regards to pH. In aqueous solution, it goes through at least three compositional phases with different properties, depending on pH:

1: High pH--lots of NaOH in there: OCl- ion.
   This is supposedly one of the stronger oxidizing species, but as it is ionic, it can't travel into a nonpolar solvent phase! (damn!)--this is why most papers on bleach chemistry use PTCs; the PTC will travel into the organic layer and take the ion with it.

2: Middle pH--from 9 to neutral or so(?): HOCl, hypochlorous acid.
   Hypochlorous acid is a weaker oxidizing agent, but it is apparently somewhat soluble in organic solvents. On commercial food processing and pool web pages, they will constantly advise you to adjust pH of water (with HCl) to get most of the chlorine in this form, as it is the most biocidal, despite being a weaker oxidizing agent (perhaps it can cross cell membranes because its oil soluble?)

3: Low pH--Cl2/chlorine,chlorine ion:
  Apparently also soluble in organic layer. HOCl + H+ Cl- <--> H2O + Cl2. This is not so different from chlorine gas, and in fact, it will apparently cause chlorine evolution if you carelessly ditch HCl in bleach.

Now, this picture is complicated somewhat by OTHER oxidizing species that can be present.

Most interesting to ning is what happens if you acidify bleach with Acetic acid. The equation changes to:
HOCl + H+ OAc- <--> H2O + ClOAc
The chloroacetate ion is a powerful oxidizer. Also, interestingly, acetic acid is a good solvent for both polar and nonpolar compounds. Ning has a paper describing just such a system, (no PTC necesary), and if the hive doesn't have this paper, ning will post it (must UTFSE first).
Also, this system may have the disadvantage of being at an acid pH. Ning wonders about the effect of using NaOAc instead of HOAc. It would introduce the OAc- ion, all right, but what then?


Also, some of the PTC systems are not using the PTC to carry the hypochlorite ion across the oil-water boundary, but rather, the PTC is actually oxidized by the hypochlorite, then travels across to the compound you want to oxidize, and oxidizes it. (The paper on TEMPO-mediated PTC oxidation). Ning would call this "transfer oxidation". This is not what we want because it seems that this type of system is much more dependent on a specific PTC's characteristics than a simple PTC oxidation system.

Ning wonders what would happen if the nonpolar compound is dissolved in alcohol/water mixture. several of the papers show that bleach can be selective for only secondary alcohols, sparing the alcohol the raging force of its oxidizing power. Whether and how well this can work remains to be seen.

Also, there is the very good possibility of taking advantage of the hypochlorite ion's difficulty in crossing solvent layers, particularly in the case of making quinone from hydroquinone. Hydroquinone is fairly soluble in water, while quinone is not, so if toluene and bleach are put together, and hydroquinone is added, either as sodium salt, or just as-is, then as the hydroquinone is oxidized to quinone, it will automatically get sucked across into the toluene layer, and be thus protected from further oxidation, or undesired chlorination. Just pour off the toluene when the reaction is done, and it contains your quinone, to do with as you please.

The only annoying thing about this whole thing is that while both the secondary alcohol to ketone, and hydroquinone to quinone reaction have been done with bleach in high yield, they are done under various conditions that make it hard to tell what is really necesary, and what is not.

Ning's reccomendation to the hive community with a strong hankerin' for OTC quinone and a little lab equipment is to do this:

Get some tylenol or whatever. Also, get some hydroquinone.

Bleach is naturally basic, so if ning's guess about the OCl- ion being good enough for this oxidation is correct, you needn't adjust its pH. Just use as is.

Now do these experiments:

1. bleach & hydroquinone. Toluene top layer. No PTC.
2. bleach & tylenol. "    "
3. bleach & hydroquinone. Toluene top layer. Add vinegar.
4. bleach & tylenol. "

evaporate the toluene, report your yields. hydroquinone is very yellow. all the (minimal) gak in the acetaminophen pill should stay in the water/bleach layer.
If yields from tylenol suck, but yields from hydroquinone are good, then the next thing to do is split off the aceto group from the amino. Ning is hoping that the oxidation will do that, but it is possible not.

To do that, just put the tylenol in fairly strong acid or basic solution and give it a little boil. In the microwave should work. If you are adding acetic acid, well, how about that...?

then do:

5: p-aminophenol + bleach
6: p-aminophenol + bleach + vinegar

Ning assumes a 2-molar excess of hypochlorite will be sufficient. Any bee got time for this?

Bleach chemistry is more complicated than it looks, eh?
But that is part of it's power--by screwing around with the ions in bleach, you can make in oxidize, hypohalogenate, chlorinate, epoxidize, oxidize only secondary alcohols, oxidize both primary and secondary alcohols, etc, etc. Very versatile reagent.

pericles

  • Guest
Some info
« Reply #25 on: November 14, 2003, 07:27:00 PM »
Sorry for the poor quality of the response, I'm quite far from my equipment and so can't provide much. I figure something is better than nothing, though.

0 min - 500mg powdered acetaminophen was added to 250ml bleach. Acetaminophen quickly turned dark orange / brown and sunk to bottom.
+5 min - White bubbles begin appearing on suface of bleach.
+7 min - The aforementioned orange / brown powder begins rising to the surface of the bleach.
+10 min - Out of concern the reaction was going too far I filter off the bleach. Bleach was noticably warm to the touch.

Filter paper has a light brown / tan coloured substance on it in addition to a white substance (tan to white ratio is around 2/3). Tan substance not easily soluable in water, isopropyl alcohol or weak acetic acid. White substance no soluable in water, others unknown.

Polverone

  • Guest
chloroacetate from TCCA?
« Reply #26 on: November 15, 2003, 03:15:00 AM »

Most interesting to ning is what happens if you acidify bleach with Acetic acid. The equation changes to:
HOCl + H+ OAc- <--> H2O + ClOAc
The chloroacetate ion is a powerful oxidizer. Also, interestingly, acetic acid is a good solvent for both polar and nonpolar compounds. Ning has a paper describing just such a system, (no PTC necesary), and if the hive doesn't have this paper, ning will post it (must UTFSE first).
Also, this system may have the disadvantage of being at an acid pH. Ning wonders about the effect of using NaOAc instead of HOAc. It would introduce the OAc- ion, all right, but what then?



Again you intrigue me. I didn't realize that chloroacetate was a good oxidizer. Chloroacetic acid has interesting uses in its own right. Do you think that one could produce significant amounts of sodium chloroacetate and TCCA in solution? That would make me as happy as a clam.

I tried dissolving some TCCA in glacial acetic acid tonight. It didn't dissolve very well. It does dissolve nicely in acetone though.

Oh, and I'm also interested in the possible conversion of primary alcohols to aldehydes with TCCA. Unfortunately, everything I've seen about that has used the exotic catalyst TEMPO to make it work.




Rhodium

  • Guest
acetyl hypochlorite, not chloroacetate
« Reply #27 on: November 15, 2003, 07:00:00 AM »
He is not talking about chloroacetate, Cl-CH2COO-, but rather acetyl hypochlorite, CH3COOCl, he just failed to use the correct nomenclature (after all, the type of compound is pretty uncommon).

ning

  • Guest
primary alcohols to aldehydes....
« Reply #28 on: November 16, 2003, 04:16:00 PM »
Well, ning might have seen the paper you saw...yes, it was an indirect oxidation. Uhh...well....good catch, rhodium...
Ning thinks bleach has a better chance to do the dirty aldehyde deed, and if ning can find that paper...it used a PTC, if memory serves, but it wasn't tempo...one of the more common quats, methinks.
If anybee can say something definitive about the oxidizing/selectivity of the different species in bleach at various pH, ning would be very happy to hear about it.

If it is of interest to the hive, ning copied something on NaOCl from "encyclopedia of reagents for organic synthesis" or something like it, it has a lot of refs.

Ning doesn't really like MnO2 as much as bleach, but it is fairly cheap, OTC, and can make aldehydes.

by the way, 40 g MnO2 from batteries lost almost 10 g after being washed with 2 liters warm water and dried. This must be the infamous electrolytes. Beware, all who would use the MnO2...wash it first. Unfortunately, ning has not yet devised a way to figure out how much carbon is in there.

pericles--great! ning likes this! Other experimentation!
There are several possibilities.
1. you got benzoquinone, with oxidized gak
2. you got partially oxidized something (like N=<=>=O)
3. you got trashed bits of acetaminophen, or chlorinated crap

Hopefully the first one :->
In ning's experience, orange/brown/black is the progression taken when the stuff is left to sit overnight after the MnO2 treatment. Try extracting with toluene. If it turns yellow, well.........that's the color of gold, isn't it?
Evaporate off solvent and smell. Supposed to be "pungent".
Wonder what they say phosgene smells like?

It may be necesary to hydrolyze the acetaminophen first, but ning suspects the strongly basic bleach may take care of that for you.

Any words, rhodium? Ning is bee shooting in the dark on this topic. Especially regarding the bleach....


ning

  • Guest
PTC Catalyzed Hypochlorite Alcohol Oxidation
« Reply #29 on: November 17, 2003, 10:13:00 AM »
Hey polverone.... ...ask, and thou shalt recieve...

Phase Transfer Catalyzed Oxidation of Alcohols with Sodium Hypochlorite
Gholam A. Mirafzal & Albena M. Lozeva
Tetrahedron Letters 39, 7263-7266 (1998)

Abstract: Phase transfer catalyzed oxidation of alcohols with sodium hypochlorite in ethyl acetate media resulted in good to excellent yield of oxidized products. These reactions are mild, efficient, and safe. The experimental procedures and work-ups are very convenient.


   Oxidation is an important type of reaction in organic synthesis and as such is used in most research laboratories. Commonly used oxidants include nitric acid which is dangerous and very corrosive, and salts of manganese or chromium which are highly toxic, mutagenic, cancer suspect agents, environmentally harmful and often messy.(1)
    In this paper, we report a safer sodium hypochlorite procedure for the oxidation of alcohols. In addition our experimental procedures and work-ups are easy, the yields of oxidation products are good to excellent, and the reaction time is short. Thus our method is even more attractive than the previously described methods for oxidation of alcohols(1-2). It is hoped that this method will have an immediate application in the way oxidation chemistry reactions, in particular, the oxidation of alcohols are performed.(3)
   Various alcohols (primary, secondary, and benzylic) were subject to sodium hypochlorite oxidation under the mild experimental conditions specified below. In all cases, good to excellent yield of oxidized products were obtained.



 R              NaOCl/R4N+Br-, RT        R
  \             EtOAc/H2O                 \
   C-OH       -------------------->        C=O
  /                                       /
 R'                                      R'

R = Alkyl Group, R' = H
R = R' = Alkyl Groups
R = Aryl Group, R' = H
R = R' = Aryl Groups



    The products were analyzed by IR, and GC-MS techniques. The absence of the alcohol OH stretch, and the appearence of new carbonyl (C=O) stretching for the oxidized products were an indication of the products' identity and the GC-MS analysis provided the molar mass and confirmed the purity of the products. Reactions were all done in ethyl acetate as the organic phase with tetrabutylammonium bromide as the phase transfer catalyst.(4) The oxidation reaction is essentially complete in 30 minutes, and the yields ranged from 72% for the oxidation of cholesterol to 93% for the oxidation of benzyl alcohol. It is essential that fresh bleach be used in order to minimize the amounts of impurities, and maximize yields of the oxidized products.(5)(for that spring fresh scent that just won't give up...) Table 1 summarizes our results for the oxidation of primary, secondary, and benzylic alcohols.(6-7)


(please forgive ning's poor chemical naming...)


Table I. Phase transfer catalyzed oxidation of alcohols with NaOCl (bleach)


1-octanol        --->  1-octanone          86%
2-phenylethanol  --->  2-phenylethanone    73%
2-octanol        --->  2-octanone          92%
cholesterol      --->  cholesterone        72%
benzyl alcohol ---> benzaldehyde       93%
9-fluorenol      --->  9-fluorenone        92%
benzhydrol       --->  diphenylmethylketone 80%

NaOCl, EtOAc:H2O, R4N+Br-, Room temp., 30 min.



    We have shown that phase transfer catalyzed oxidation of primary, secondary, and benzylic alcohols with sodium hypochlorite results in good to excellent yields of the desired oxidation products. This method of oxidation is mild, efficient, and safe. The experimental procedures and work-ups are very convenient.(7) In addition, the low cost and availability of sodium hypochlorite as commercial household bleach makes this method of oxidation of alcohols very attractive.

Refs & Notes

(1.) TL 1968, 3363; TL 1975, 2647; TL 1979, 399; Synth. 1980, 223; TL 1985, 1699; JCS-perkin 2 1979, 788; Synth. 1979, 134; Vogel's 5th, 668; TL 1998, 3815.

(2.) TL 1982, 4647; This article reported successful oxidation of sec. alcohols using NaOCl in AcOH. However, this method is not effective for oxidation of pri. alcohols and alcohols containing double bonds. It is reported that oxidation of prim. alcohols leads to dimeric esters under the acidic condition described. (in good yields, too!) For instance, oxidation of 1-decanol leads to decyl decanoate as the major product. Also oxidation of alcohols contg. double bonds is reported to produce chlorine-contg. products. Reaction times are long, they typically require 4-6 hours for completion. In addition, reagents used are potentially dangerous. Glacial acetic acid is corrosive and causes burns (so does bleach...); the vapor is extremely irritating to mucous membranes and the upper respiratory tract, and a sodium hypochlorite solution in glacial acetic acid emits chlorine gas, which is a respiratory and eye irritant. (yeah, let's just drink your bleach concoction, eh, mr. man? These academic pissing contests disgust me. I thought science was about escaping darwinistic win/lose mode of living?) We believe our method of phase transfer catalyzed oxidation of alcohol in ethyl acetate is superior over this both in terms of its application and safety consideration.(and we will duel with any who disagree...pistols at 10 paces)

(3.) This paper was presented in the Div. Chem. Ed. at the 213th ACS Nat. Mtg. in San Francisco, CA, April 13-17, 1997 (abstract #100).

(4.) In absence of PTC, little or no reaction is evident, and the alcohol is recovered unchanged.

(5.) Other commercial bleaches work as effectively when used fresh. For precise work, samples may be titrated according to the proceedure of Kolthoff, I.M.; Belcher, R. Volumetric Analysis, Interscience: New York, 1957, P. 262.

(6.) Materials & Methods: 1-octanol, 2-phenylethanol, 2-octanol, cholesterol, benzyl alcohol, 9-fluorenol, benzhydrol, tetrabutylammonium bromide, ethyl acetate, dichloromethane were all purchased from Aldrich and were used as such without further purification. TLC was performed on Eastman Kodak TLC plates (coated film, #13179) with a fluorescence indicator. Commercial chlorox fresh scent bleach (5.25% NaOCl) was used. FT-IR were performed neat or as solutions in dichloromethane on a Nicolet 510P Spectrometer. The low resolution mass spectra (LRMS) were obtained on a HP 5970 GC-MS spectrometer equipped with an HP-1 cross-linked methyl silicone gum (12m x 0.2mm x.33mm film thickness) capillary column. The inital column temp. of 60 C (1 min) then 10 C/min increments up to 250 C (15 min) were used.

(7.) General procedure:
In a 50 ml RBF equipped with magnetic stir bar, 5.56 mmol of the alcohol and 15 ml of EtOAc were mixed. The solution was vigorously stirred at room temp, and while stirring, 15 ml of commercially available Clorox Fresh Scent Bleach (5.25% NaOCl), and 0.3 g (0.93 mmol) PTC Bu4N+Br- were added. The progress of reactions was monitored by TLC using hexane:EtOAc (8:2 v/v) as the mobile phase. Oxidation reactions were essentially complete in 30 min., but in some cases the reactions were allowed to stir for a period of 1 h to insure the complete oxidation process. The organic phase was removed and the aq. layer extracted with 20 ml EtOAc or Et2O. The combined organic layer was then washed once with 20 ml of water, and then dried over MgSO4. After removal of drying agent by filtration, and removal of the volatile materials under reduced pressure, the percent yield were calculated. The GC-MS and IR analysis of the products were conducted in dichloromethane solvent. Both confirmed that the products were pure and contained no starting materials.

blah blah blah

Microscale oxidation reactions using 0.556 mmol of the appropriate alcohol, 1.5 ml of EtOAc, 1.5 ml of bleach, and 0.03 g (0.093 mmol) of PTC produced a similar yield of products but in a shorter period of time, about 20 minutes.


Look for more soon!


ning

  • Guest
Why ning thinks bleach can make quinones....
« Reply #30 on: November 17, 2003, 11:55:00 AM »
J. Chem. Research(S), 1999 pg. 672

Sodium Hypochlorite/Dowex 1x8-200: An Effective Oxidant for the Oxidation of Aromatic Amines to Quinones

Mohammed. M. Hashemi & Yousef A. Beni

Polymer-supported hypochlorite ion is a useful oxidant for the oxidation of aromatic amines to the corresponding quinones.


Organic reactions on supported reagents have recieved recently considerable attention from synthetic chemists because of their high efficiency, environmental safety and convenient work-up procedures. (1-3) Polymer supported reagents have emerged as a complementary approach to solid phase organic synthesis. (4,5) Reagents supported on insoluble polymers are particularly convenient for solving many problems in organic chemistry. (6-8)
   Sodium hypochlorite is a readily available and inexpensive oxidant and has been used for the oxidation of variety of compounds.(9) Unfortunately, the traditional NaClO oxidation methods such as oxidation under phase-transfer catalyst have been developed. (10,11) However these methods possess disadvantages, e.g., long reaction times, high temperatures and use of expensive polar aprotic solvents.
   We have now found that it is possible to obtain in a simple way a polymer supported ClO- reagent for the oxidation of aromatic amines to quinones utilizing a commercial anion exchanger resin.
   Oxidation of aromatic amines to quinones is an important reaction in organic chemistry and a variety of oxidizing reagents such as potassium dichromate,(12) potassium nitrosodisulfonate,(13 ferric chloride,(14) sodium nitrate,(15) silver oxide and lead dioxide,(16) lead tetraacetate(17) and hydrogen peroxide(18) have been developed. Most of the reported reagents require vigorous conditions, (12,13,15) some require tedious workup, (17) give low yields (15,16) or long reaction times. (14,19)
    We report here the use of hypochlorite ion on Dowex 1X8-200 as an inexpensive alternative for oxidation of aromatic amines with total selectivity  to the corresponding  quinonones. Table I lists a variety of aromatic amines oxidized with supported ClO- on Dowex 1X8-200 anion exchanger resin to the corresponding quinones.


Table I Oxidation of aromatic amines to quinones

R-C6H4-NH2 --->  R-(O=C6H3=O)

*bzq = benzoquinone, npq = napthoquinone, DME = 1,2-dimethoxyethane
                                 g resin
Amine                Product      /mmol   solv. time  yield
---------------    ------------   ------  ----  ----- ----  
Aniline               1,4-bzq        1.5  THF     30  88%
2-Toluidine           2-Me-5-bzq     2    THF     30  93%
3-Cl-aniline          2-Cl-1,4-bzq   1.8  THF     45  85%
1,2-phenylenediamine  1,2-bzq        2    CH2Cl2 150  95%
2-aminophenol         1,2-bzq        2    EtOAc  150  91%
4-aminophenol     1,4-bzq     2   DME   45  97%

2-toluidine           2-Me-1,4-bzq   1.5  THF     30  95%
1-aminonapthalene     1,4-npq        1.8  DME     45  90%
1-amino-2-napthole    1,2-npq        2    DME    150  89%
1-amino-4-napthole    1,4-npq        2    DME     85  93%



Experimental:

All melting points are uncorrected. IR spectra were recorded (KBr) on an FT-IR unicam mattson 1000 spectrophotometer. 1-H NMR spectra were recorded on a Bruker ac-80 (80 Mhz) spectrometer in CDCl3 and chemical shifts are indicated in delta. Chemicals were purchased from Merck, Aldrich and Riedel AG and were used without further purification. All products are known compounds and were identified by their mp, IR, and NMR properties. All yields refer to isolated products.

Preparation of ClO- supported on an anion exchanger resin:
To prepare the reagent, 55g of the chloride form of Dowex 1X8-200, a macroreticular anion exchanger resin containing quaternary ammonium group, was added under stirring to a 200 ml solution of 1.85 M NaOCl. Chloride ions were readily displaced and the ClO- form of the resin was qaulitatively(?) obtained in 2 h. The resin was then successively rinsed with water, acetone and absolute ethanol and finally dried in vacuo at 65 C for 5 h. The capacity of the resin was determined by stirring 1.0 g of the resin overnight with 20 ml of 2 M aqueous KOH, filtering off and titrating iodometrically. In the obtained hypochlorite solution, the determined average capacity of the dried resin was 2.2 mmol ClO- per gram of resin.

Oxidation of Aromatic amines into quinones: general proc.

Aromatic amine (2mmol) and the dry ClO- form of the resin (1.5 g) were refluxed in 25 ml of dry THF under vigorous stirring for 30 min, then the reaction mixture was filtered through sintered glass and the filtrate concentrated and worked up with 1 M HCl. Flash chromatography (hexane-EtOAc 8:2 v/v) gave the corresponding quinone.

refs

(1) Synth. 1979, 401; 481
(2) T 1996, 4527
(3) T 1997, 5643
(4) TL 1996, 7193
(5) Synth. 1997, 1217
(6) JACS 1976, 6737
(7) TL 1981, 663
(8) TL 1995, 1359
(9) Oxidation in Organic Chemistry, ACS, DC, 1990
(10) TL 1976, 1641
(11) TL 1998, 1641 (wierd!)
(12) T 1986, 5065
(13) Chem. Ber. 1959, 674
(14) Org. Syn. CV2 430
(15) Org. Syn. CV3 633
(16) Chem. Ber. 1906, 3482
(17) JACS 1950, 4601
(18) JOC 1993, 3633
(19) Handbook of anion determination, Butterworth & Co. Ltd. London, 1979
(20) CRC Handbook of data on organic compounds 1989


----------------DISCUSSION----------------


This is one of those papers that does the impossible, in good yields, with mild, nontoxic reagents under room temperature and pressure. All you need for a catalyst is the philosopher's stone....or so it would seem. I know I can't find dowex anywhere easily, although if I really wanted it, maybe a water softener would have some. But that's not the point.

Look at what they oxidize, to get what! With what!
p-aminophenol to p-benzoquinone with hypochlorite ion
Now, as far as I understand, that "macroreticular anion exchanger resin" is just the same thing as a quaternary ammonium PTC, except it is embedded in plastic instead of free. This naturally makes workup much nicer, but it points us to some important points:

1. It is the ClO- ion which is doing the oxidizing, not the PTC or resin. (no TEMPO-mediated transfer oxidations here)

2. The resin is more or less exchangeable with a PTC

3. The only reason to use a resin or PTC in this case is to get the stupid organic compound to come into the water layer where the hypochlorite ion is.

Now bleach already has plenty of hypochlorite ion in its basic state, so we should concern ourselves with how to get our lovely aminophenol down there to meet it.

Maybe for other compounds this would be a problem, but since p-aminophenol has a phenol group, which can be "salted" with NaOH, which bleach happens to have a lot of in it too. That will ionize it and make it soluble. Maybe the oxidation depends on the phenol not being salted? I don't think so, just look at all the crap they oxidized...aniline worked well too, so I think it probably doesn't matter so much what is attached to the stupid amino group. Also, if there is an acetyl group on the amino, under the basic conditions, its very likely to get hydrolyzed off...sounds pretty easy to me.

So, I wonder if they even bothered to try disolving the p-aminophenol in bleach without all that other trickyness with anion exchangers, etc. Maybe if they did, they wouldn't have so much to write about, eh?

So, acetaminophen in strongly basic bleach, with or without acetone or alcohol cosolvent. 1,2-dimethoxyethane is ethylene glycol dimethyl ether, boiling at 85 C. Ethanol might substitute(bp 78), while acetone boils low (56 C), but has been used in bleach oxidation papers very nicely. Ethyl Acetate would probably be hydrolyzed. Anyway, select your cosolvent, boil and stir for a while. Extract with nonpolar solvent. I would expect the stuff would become a crud or oil and float to the top, as it's not water soluble.
No PTC necesary, thinks I. Nor ion-exchanger resin.

Another piece falls into place. I see no theoretical reason why a simultaneous oxidation of ring and chain couln't happen, yielding the desired 1-(2,5-benzoquinone)-2-propanone, ready for HCl/HBr addition and methylation.

Comments?


Chimimanie

  • Guest
quinone, rambling and dowex
« Reply #31 on: November 17, 2003, 07:15:00 PM »
Good work Ning. :)

Another piece falls into place. I see no theoretical reason why a simultaneous oxidation of ring and chain couln't happen, yielding the desired 1-(2,5-benzoquinone)-2-propanone, ready for HCl/HBr addition and methylation.

I would prefer to have the isopropanol in place of the ketone, as according to

Post 358239

(poix: "2,5-dimethoxy-phenylacetone from o-Allylphenol", Novel Discourse)
the 1-(1,4-Benzoquinonyl)propan-2-ol rearrange itself to 2,5-dihydroxy-P2P in reasonable yield (70%) by sunlight.

But of course the quinone can be reduced selectively to the hydroquinone while keeping the ketone untouched with Na2S2O4 (hydrosulfite, dithionite) in great yield too.

One question: how would you want to put the side chain on the quinone?

EDIT: now that i have read the whole thread i see what you are aiming at. Personally i would prefer going this type of route from p-methoxyphenol than paracetamol, and halogenate the ring at the end of the synthesis, like usual.

Concerning the chlorination of the alkylated quinone, you may find

this article J.Serb.Chem.Soc. 67(8–9)547–551(2002)

(http://www.shd.org.yu/HtDocs/SHD/Vol67/No8-9/V67-No8-9-01.pdf) interesting.


One of the viable way I am seeing is by hydrolysis, then oxydative decarboxylation of the acetal of ethyl acetoacetate, if the acetal resist such conditions, to yield the radical of acetone and quench it with benzoquinone with a dash of silver nitrate in the medium, like

Post 264250

(halfapint: "Re: alkylation of quinones", Novel Discourse)
suggested. But again acetoacetate is not OTC. The (non-posted) mercury acetamidation stay the best way to DOX compounds in OTC fashion IMHO as mercury, propylene, and acetamide are all OTC (or easy to make). (hint: think more about this:

Post 426454

(Chimimanie: "Dimethoxy-phenylethyl alcohols", Novel Discourse)
)  ;)

Also yes Dowex are used in all sort of washing machine, like to wash clothes or kitchen plates. The NaCl they add in their shitty two color tablets is used to displace the different ions from the resin to evacuate them and free the resin to catch new ones.

ning

  • Guest
Hmm...some good shit...
« Reply #32 on: November 18, 2003, 02:30:00 PM »
Thats some good info. Ning likes.
Only thing ning wonders, what's wrong with the allylation/claisen rearrangement method? It's OTC, and relatively easy (oxalic acid + glycerine, boil boil boil--->allyl alcohol, add dry HCl, ---> allyl chloride)
Or, if you have iodine and RP handy, one step to allyl iodide.

Then, mix your acetaminophen with the stuff in NaOH, and it should O-allylate. Perform the Claisen rearrangement by heating it real toasty, and it will become an aryl allyl. These two steps can be done in one pot, and ning has 3 or 4 papers discussing the making of allyl alcohol and allyl chloride. If you do it this way, ning thinks it is better to use acetaminophen than hydroquinone, as the acetaminophen can only alkylate in one place (right???), whereas hydroquinone might be tempted to alkylate twice. Also, while ning wanted to directly alkylate in the past, it now seems more efficient to do the O-allylation/claisen rearrangement way. (See rhodium's page, or Orgsyn.org under Eugenol) The rearrangement way has good yield.

And ning can definitely understand the attraction of p-methoxyphenol, but since you still need to methylate it (just once instead of twice), and you need to chlorinated or brominate the ring, which is easier using the quinone modality than otherwise, it seems to ning not to bee much simpler or easier to use p-methoxyphenol than acetaminophen. And where is p-methoxyphenol otc? Ning may have uses for such a thing. But ning hasn't seen it. Ning's dream is psychedelics for the people-- a synthesis of a drug that is so powerful that a kilo can supply a whole city, so OTC that every precursor can be bought off the shelf no questions asked in every supermarket and hardware store, and so easy that your average meth cook or college student could do it. To render the drug war obselete, through chemistry. Or as close to it as possible. That is ning's dream. And plus, since acetaminophen is the usual gak "they" use to poison other drugs with, to use it as the main precursor in such a synth has a touch of divine, poetic justice to it. Since acetaminophen is the gak they use to gak everything else, what will they gak it with? I think I hear the gods laughing quietly...


Those are some good links though. Ning will read, and expand knowledge. Ning's power and focus is devoted to this goal.

A bit of info, for those who are watching with interest: Ning had a fitful night, and dreamt of something....

10 mmole acetaminophen, as powdered tablets.
50 mmole NaOCl as bleach
70 mmole NaOH, for the following purposes:
10 mmol for "salting" with the acetaminophen
10 mmol for hydrolyzing off the acetyl
10 mmol for good measure.
50 mmol just in case the bleach needs it.

The total volume came to about 100 ml.

two runs were performed: one with acetone, one without.

1st run:
The lye was dissolved in the bleach. Nothing happened. The acetaminophen was swirled with the acetone and poured into the bleach. A very vigorous and exothermic reaction followed, with the acetone/acetaminophen mixture turning midnight black immediately. A strange smell emenated from the flask, and there was much boiling. After some time, a yellow bubbly crust formed in the top of the flask.

Worried that the bubbling bespoke of some awful fate for the acetone, (after reading about base-catalyzed haloform reactions....), the dreaming chemist performed another run.

This time, half the lye was dissolved in a small beaker, and the acetaminophen powder poured in. It instantly turned light muddy brown, which ning takes to be the hydrolysis reaction to p-aminophenol. It also dissolved in this form, which was very convenient. This mixture was then dropped into the bleach and stirred. The reaction was again exothermic, and the same midnight brown was observed. A very obnoxious, foul odor evolved from the flask. The bubbling was noticeably less than the last run. The flask was placed outside with a card over it to let it run, and left overnight.

Ning lost the dream here, and after some irrelevent fluff, got it back again.

It was morning, and the chemist took the second run's flask and examined it. There was the same yellow layer on top, although noticeably smaller. When a stirring rod was dipped into the black/brown gunk, it came out with a yellow coating. It would appear that the mix was actually yellow, but too bloody opaque to see.
No, you know what, it looked like

this

(http://www.uni-regensburg.de/Fakultaeten/nat_Fak_IV/Organische_Chemie/Didaktik/Keusch/p15_chinhydr-e.htm)

hmm, how interesting.

The workup is where the dream stopped. It would seem that the chemist was unaware that acid workup is necesary, as quinone is soluble in alkaline soluttion. So after trying to get it into toluene with no success, the chemist dropped sulfuric acid into the mix (now in separatory funnel), and stirrrrred it, succeding only in creating a VICIOUS emulsion. Addition of salt didn't help much. That's where the dream ended. Such a sad thing.

so, bees, could it be a quinhydrone our strange chemist had? how annoying, if that was the case. And the need for the acid workup? Seems like it needs a hydrolysis to finish? More dreaming is in order. Lets see who the sandman visits with his glassware next?

ning

  • Guest
that serbian paper is nice...
« Reply #33 on: November 18, 2003, 02:46:00 PM »
and if you have NaOEt and EtOAc, you can make ethyl acetoacetate,(orgsyn) which ning bets you could hydrolyze to acetoacetic acid. So it is concievably OTC, but if you have NaOEt, you might as well just use the drone enolate synth with acetone...
Mind you, that is one thing ning has been trying to do with that Sodium Oxide crap...So ning is working on it...That EZ-iodation with KNO3, combined with some NaOEt or NaOiPr and acetaminophen also has some good potential.

Ah, well.

Chimimanie

  • Guest
Why i prefer p-Meo-phenol?
« Reply #34 on: November 18, 2003, 05:47:00 PM »
Because it is cheap, OTC, and there is plenty ref on claisen reaction with it. Acetaminophen is an expensive substrate and if you want it OTC you have to extract it from shitty pills, that i will never do. I do not extract pills like the usual meth moron. Its all about proud to bee a bee that do not give away money to Big Pharm's Co whose policies i do not like.

And ning can definitely understand the attraction of p-methoxyphenol, but since you still need to methylate it (just once instead of twice), and you need to chlorinated or brominate the ring, which is easier using the quinone modality than otherwise, it seems to ning not to bee much simpler or easier to use p-methoxyphenol than acetaminophen. And where is p-methoxyphenol otc? Ning may have uses for such a thing. But ning hasn't seen it.

-To methylate once instead of twice is cheaper.

-Bromination of the ring is a breath from DMA, if DOB is your target you should not care about legality. For the chlorination i think too the quinone as some good potential, but using the quinone only for that is waste of good reactant, you should aim to use the quinone to put a correctly substituted side chain on ring without passing through the two or three steps of allylation, thermal claisen rearrangement and further side chain processing. From quinone those steps could bee reduced to one or two.

-p-methoxyphenol is OTC from hydroquinone following the work of Antoncho, or from cheap and avaiable anise oil following Dakin reaction.


I will give you some refs to chew:

-First: a Claisen on p-Meo-phenol (as well as on sesamol for TMA-2 freaks) from

Patent US5977117

:

Example 17:

a. Allyl 3,4-(methylenedioxy)phenyl ether:

Allyl bromide (1.75 g., 14 mmol) was added to a solution of sesamol (2.0 g, 14 mmol) that had been dissolved in 50 ml of dry acetone, followed by addition of powdered potassium carbonate (2.4 g, 17 mmol) and the resulting cloudy solution was refluxed for 18 h. The solution was cooled and the solvent removed in vacuo. The remaining suspension was extracted into ether and the organic layer was washed with water (1 x 25 ml), brine solution (1 x 25 ml), and dried over MgSO4. Concentration of solvent yielded 2.4 g (94%) of a pale yellow oil which was used in the next step with no further purification.

b. 2-allyl-4,5-(methylenedioxy)phenol:

A solution of allyl 3,4-(methylenedioxy)phenyl ether (2.4 g, 13 mmol), was dissolved in 30 ml of 1,2-dichlorobenzene and the solution was refluxed for 18 h. The solvent was removed under high vacuum in a water bath set at 60°C. The remaining oil was extracted into ether, washed with brine and dried over MgSO4 The solvent was removed under vacuum to give a yellow oil which was further purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes gave 2.2 g (92%) of the pure compound as a pale yellow oil.

Chimimanie's comment: The 1,2-dichlorobenzene can bee replaced by another high-boiling solvent, or by melten predistilled moth ball (1,4-dichlorobenzene), and workup can bee basic aqueous extraction instead of solvent evaporation.

Example 22:

a. Allyl(4-methoxyphenyl)ether:

Allyl(4-methoxyphenyl)ether was prepared in the same manner as described in Example 17a, but using 4-methoxyphenol (10 g, 84 mmol) and allyl bromide (9.7 g, 84 mmol), in 98% yield as a yellow oil.

b. 2-Allyl-4-methoxyphenol:

2-Allyl-4-methoxyphenol was prepared in the same manner as described in Example 17b, but using allyl(4-methoxyphenyl) ether (13.0 g, 79 mmol). Column chromatography using 10% ethyl acetate-hexanes resulted in 11.6 g (89% yield) of the pure phenol as a pale yellow oil.

also check

https://www.thevespiary.org/rhodium/Rhodium/chemistry/25.meo.allylbenzene.html



and the whole thread here

Post 428230

(pHarmacist: "New, promising route to DOX series?", Novel Discourse)
with various synthesis of allyl halide posted too.


-You will bee happy i found this patent for a part of your route:

Patent WO9320807

check example 1 p 27-28/69:

Preparation of 4-acetamido-2-allyl-phenol:

Commercially available 4-acetamido phenol (1 molar equivalent), allyl bromide (1 molar equivalent) and potassium carbonate (1 molar-equivalent) in butan-2-one were heated at reflux for 18 hours with stirring. The mixture was cooled, filtered and the solid residue washed with ether. The combined filtrates were evaporated and the solid residue was further purified by cristallisation from ethyl acetate-hexane to give 4-acetamido-1-allyloxy benzene as a colourless solid, mp 85-86°C.

The above allyl-ether was heated under reflux in diphenyl ether for 0.16 hours. The cooled reaction mixture was diluted with diethyl ether and then extracted with sodium hydroxide solution (2M). The aqueous extracts were combined and then acidified (10M HCl). The aqueous phase was extracted with ether. After evaporation of the ether, the oily residue was triturated with hexane to give a solid which was further purified by recrystallisation from ethyl acetate-hexane to give 4-acetamido-2-allyl phenol as a colourless solid, mp 82-85°C.

also check JMC 1995 38(21) 4157-60 and JACS 1998 120(12) 2963-2964 maybe the yield will bee given in those refs.


-I didnt found the hydrolyse of the amide to the amine, but i found a preparation of 4-amino-2-allylphenol from sulfanilic acid, sodium nitrite and 2 allyl-phenol in

Patent US3723118

:

(4-amino-2-allylphenol hydrochloride):
 
While a solution consisting of 97 g. of sulfanilic acid, 39.2 g. of sodium carbonate monohydrate and 1 liter of water was maintained at 8°C, 168 ml. of concentrated hydrochloric acid and then 40.6 g. of sodium nitrite dissolved in a small amount of water were added to obtain a reaction mixture containing white diazonium salt.

The resulting mixture was added to a solution composed of 112 g. of caustic soda, 164 g. of sodium carbonate monohydrate, 75 g. of 2-allylphenol and 2 liters of water with stirring, wherein the temperature of the reaction mixture should be kept below 5°C in a water bath. After the addition, the water bath was removed and, after stirring for an hour, 400 g. of sodium hydrosulfite was added thereto followed by heating to 70°C to provide precipitated white crystals of the amine. After cooling, the crystalline amine was collected and converted into its hydrochloride, whereby 67 g. of 4-amino-2-allyl-phenol hydrochloride, as colorless crystals having a melting point of from 177 to 190°C (decomposed), was obtained in a yield of 64.4%.

From glycerol/oxalic, nitrobenzene, Tin, sodium nitrite and sulfuric acid all needed precursors can bee made.

The abstract of JACS 1917, 39 2188-224 tell us this:

o-Allylphenol, bp (22) 109-10°, is obtained practically quant, by isomerization of CH2:CHCH2OPh by Claisen's method; with NaOH, NaNO2 and AcOH it gives p-nitroso-o-allylphenol, yellow-brown crystals, m. 99.5-100° (partial decompn.), reduced by NH3H2S to 2-allyl-4-aminophenol, leaflets, m. 112.5-3.5°




check also at the same time JACS 1958, 80 3271-7, and if you understand german, check the old Claisen's article which describe both compounds : Ann. 1919 418 69-120.


- Now speaking about the potential of quinone, i think you should check this ref (I haven't now but it look promising).

Chem. lett. 1992 7 1299

The abstract describe a reaction of monoallyl-oxalic acid ester with quinone and silver/persulfate to yield the allyl quinone (para-to an alkyl group to yield DOM precursor too) in 90%+ yield. I hope it turn to be a good paper.

Otherwise a chinese  :(  paper (Huaxue Xuebao 1991 49(8) 827-32) say: quinone + allyl-Br + Sn metal in THF/H2O, then FeCl3 give the allylquinone in 48% yield. Various other papers deal with organo-tin compounds, but this one use metallic tin instead of organometallic tin compounds, too bad I cannot understand chinese.

Some refs I didnt check about quinones here:

Helv chim acta 1984 67(5) 1406
Free radical research 2001 35(1) 63
JCS (C) 1966 18 1627
JCS (abstract) 1965 5060



Enjoy the refs, but i will not change my mind, HQ --methylating agent--> 1,4-DMB --Hg2+, acetamide, propylene--> acetyl-DMA --iodination--> acetyl-DOI --basic hydrolysis--> DOI stay unbeaten in my mind.


ning

  • Guest
welll....
« Reply #35 on: November 18, 2003, 06:54:00 PM »
more good stuff...that ref on the claisen with p-aminophenol ester is a good'un.

BUT...dude...you're bent. ;)


Acetaminophen is an expensive substrate and if you want it OTC you have to extract it from shitty pills, that i will never do. I do not extract pills like the usual meth moron. Its all about proud to bee a bee that do not give away money to Big Pharm's Co whose policies i do not like.


It's nothing like extracting ephedrine, I promise you. And nowhere near as expensive as you seem to think. I bought 250g for $7, and a 500mg pill weighs 550mg...about 1% gak. Not the most challenging of extractions.


From glycerol/oxalic, nitrobenzene, Tin, sodium nitrite and sulfuric acid all needed precursors can bee made.


ummm...you're kidding, right? NaNO2 is hardly a trivial thing to make, tho' I know it can be done. Tin metal is not that easy to find in bulk either, maybe you have a trick.
And how, in the name of the seven demons, are you going to make nitrobenzene? Easily? From benzene? Halfapint might have liked to hear that trick, for his lignin syringaldehyde work.

And you are trying to imply that all of these things together are cheaper than buying a bottle of pills and crushing them up? Less than 7 bucks for 250g? How much is your time worth??

To methylate once instead of twice is cheaper.

Umm...the methylating agent I am investigating is not the most expensive of things...oxalic acid & methanol, in 1 step. I don't mind if it needs twice the amount. Even if I have to make DMS, it's still not the hardest of things to double the batch size.


Chimimanie's comment: The 1,2-dichlorobenzene can bee replaced by another high-boiling solvent, or by melten predistilled moth ball (1,4-dichlorobenzene), and workup can bee basic aqueous extraction instead of solvent evaporation.


not to bee a nitpicker, but have you ever smelled that stuff? It sublimes at RT, so I don't want to imagine the smell at reflux. Hope you have a stink pipe.


I didnt found the hydrolyse of the amide to the amine, but i found a preparation of 4-amino-2-allylphenol from sulfanilic acid, sodium nitrite and 2 allyl-phenol in Patent US3723118:


Well, thanks...umm...it is just a little heat & stir in NaOH, but anyway...

Thak you for all the hunting & searching you have done, I appreciate it. And if you have all those chemicals, synth away, with my blessings. I especially appreciate the ref on the claisen rearr. w/ p-aminophenol.

Some of those suggestions seem very dubious, tho...lets not complicate things too much here. No NaNO2....

peace 8)

Chimimanie

  • Guest
Its all about sources
« Reply #36 on: November 19, 2003, 03:03:00 AM »
From glycerol/oxalic, nitrobenzene, Tin, sodium nitrite and sulfuric acid all needed precursors can bee made.

ummm...you're kidding, right? NaNO2 is hardly a trivial thing to make, tho' I know it can be done. Tin metal is not that easy to find in bulk either, maybe you have a trick.
And how, in the name of the seven demons, are you going to make nitrobenzene? Easily? From benzene? Halfapint might have liked to hear that trick, for his lignin syringaldehyde work.


All those chems are OTC in my neck of the wood.  ;)  Easier to find in quantities than acetaminophen too, we do not have it at your price OTC here, my nation is less medicated than yours it seems... NaNO2 is a very easy aquisition for me, I will never make it...

Umm...the methylating agent I am investigating is not the most expensive of things...oxalic acid & methanol, in 1 step. I don't mind if it needs twice the amount. Even if I have to make DMS, it's still not the hardest of things to double the batch size.

By the same time you are playing with dimethyloxalate, try to trans-esterify it with allyl alcohol in basic media please.... From the diallyl oxalate, the monoallyl can bee made easily:

Patent JP03223231



Abstract

RO2CCO2M (R = C1-6 linear or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl, benzyl, methoxybenzyl, nitrobenzyl; M = alkali metal), useful as intermediates for antibiotics and allergy inhibitors (no data), are prepd. by hydrolyzing RO2CCO2R using MHCO3.  Thus, diallyl oxalate was stirred in aq. KHCO3 at 75-85° for 4 h to give 97.6% monoallyl oxalate K salt in 97.2% selectivity.

not to bee a nitpicker, but have you ever smelled that stuff? It sublimes at RT, so I don't want to imagine the smell at reflux. Hope you have a stink pipe.

Hehe, yes it is a bit toxic too,  ;D  but other high-boiling solvents are avaiable... BTW have you ever smelled allyl formate?  ;)

Well, thanks...umm...it is just a little heat & stir in NaOH, but anyway...

After some lab work you will learn to cover your ass with some references, its better time-wise and precursor-wise.  ;)

Also DMS or acetoacetate are not considered easy things to make in my oppinion.

Now I will devote my time to my ~OTC indigo to AMT synthesis...  8)  Good luck with your DOX from acetaminophen route.  ;)

ning

  • Guest
Your neck of the woods
« Reply #37 on: November 19, 2003, 12:35:00 PM »
must not be in america...the most medicated, the least precursors. Or so it would seem...

You have a remarkable patent sourcing ability...but sometimes they don't make sense to me...what could bee done with sodium oxalate allyl ester? Perhaps you're thinking of skipping the allyl-alcohol to allyl chloride step somehow? I don't understand exactly.

I looked up that JACS ref, but it seemed to be on enzymes or something unrelated to quinones. Will look again.

And I say, that hydrolysis is just a hydrolysis! Nothing too fancy about it! Acids or bases, both will do...and you have to go to the right store to get the acetaminophen/paracetemol. You don't go out and buy tylenols, of course. You go to (american) k-mart, or possibly one of the larger supermarkets with a pharmacy. Then you look for the store brand tablets, in a big bottle. Don't accept anything less than 500 tablet bottle of 500mg's, for no more than ~$10US. Acetaminophen is somewhat unique among medicines (although aspirin is similar), because it can basically be made out of coal tar in a few steps, making it more of a "commodity material", and less of a "fine drug". Certainly its synthesis is a lot simpler than, say, pseudoephedrine or something like that.

phenol + HNO3 --> p-nitrophenol ---> p-aminophenol --> acetaminophen
seems like one industrial route. Using gas-phase nitration and hydrogen reduction, its about as easy to make as TNT...maybe p-aminophenol is used in photography because it is a precursor? Or maybe acetaminophen is popular because p-aminophenol is produced in large bulk? hmmm...

Good luck with your...indigo route...ummm...I hope when you say OTC, you mean OTC in my sense of the word too... ;D

----now, for the good stuff---

The easy way to tell if the stoopid acetaminophen has hydrolyzed or not is whether it dissolves in water. It's not very soluble at all. But if you use an acid hydrolysis, both products should be water soluble, and it will dissolve.

Another run was dreamt, this time using sodium dichloroisocyanurate from spa chlorinating agent. Ning realized, while watching this, how useful TCCA is, as it is soluble in organic solvents, while DCCA and NaOCl are not.

The same dark color, the same abomidable smell. A drip of methanol was added, and there were some bubbles. Some soap was added, to no noticeable difference. What the hell?

Ning wonders why it always goes black. Isn't quinone supposed to be pale yellow?

Ning contemplates acquiring dowex....

Anybee have an idea what could be happening?
If there was a wild dreamer with tylenol, bleach, and a spectrophotometer or NMR access, ning would be a happy bee indeed.

ning

  • Guest
Hydrolysis/Deacetylation of p-aminophenols
« Reply #38 on: November 20, 2003, 02:14:00 PM »
Here is another step covered. While the literature is full of information on this kind of reaction (Beilstein gives ~250 hits), hydrolysis seems to be considered a trivial step, not worth documenting or optimizing, so finding good papers is not so easy. Nonetheless, ning, ever-faithful servant of the hive that zee is, managed to dig up a paper covering this critical step of the Ubiquitous Psychedelic Amphetamines Project.

JACS 1948, 1363: Aminoalkylphenols as Antimalarials.
It's a long one, and mostly fluff, so go to page 1372, where you will see This:

4-amino-alpha-diethylamino-o-cresol dihydrochloride (SN 12,458)--
A mixture of 500 g. (2.12 mole) of 4-acetamido-alpha-diethylamino-o-cresol and one liter of 20% HCl was heated at refluxing temperature for an hour. The solution was evaporated under reduced pressure to a thick sirup. A liter of benzene was stirred well into the sirup, and the evaporation repeated using a liter of denatured absolute alcohol. Finally, the sirup was dissolved in two liters of alcohol. The desired salt was then precipitated by the addition of a liter and a half of ether. A total of 541 g. (96% yield) of off-white product was obtained.

blah blah blah, they get good yields for other deacetylations.

Now, ning has many other papers covering deacetylations, but they will bee posted to the tryptamines forum ;)


Tengo

  • Guest
Does it get any easier than this?
« Reply #39 on: November 21, 2003, 09:28:00 AM »
[Edited]

1. Oxidate acetaminophen with hypochlorite in water to N-acetyl-quinoneimine. Easy as hell according to:

http://l2.espacenet.com/espacenet/bnsviewer?CY=gb&LG=en&DB=EPD&PN=EP1068177&ID=WO+++9952860A1+I+



2. Acid hydrolysis yields benzo and acetamide

3. Methylate (OTC) with:
    
     dimethyl oxalate (requires a sulfite-shake BQ -> H2Q)
     H2Q + DMO -> 1,4-DMB (according to ning)
    
     or
    
     SnCl2 + MeOH
     BQ + MeOH + SnCl2-> 1,4-DMB

4. 1,4-DMB + Mn(OAc)3 + acetone -> 2,5-dimethoxy-P2P

https://www.thevespiary.org/rhodium/Rhodium/chemistry/p2p.manganese.html



5. Aminate

DOB!

All OTC, safe and easy...