bobpage
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Replacement of GAA in bleach oxidations
It is known that bleach can be used to oxidise borneol (amongst other things) in conjunction with glacial acetic acid (The Oxidation of Alcohols and
Ethers Using Calcium Hypochlorite, S.O. Nwaukwa et. al., Tetrahedron Letters 23(1), 35-38)
Somewhere else (can't remember) it was stated that hypochlorous acid (HOCl) formed in-situ is the driving force behind the reaction.
Now, would it be feasible to replace the GAA with another weak organic acid such as citric or tartaric acid? I realise there is a downside in that
these other acids are not misicble with borneol (as GAA is), but..
If the acid was reacted with the bleach first, then the alcohol added with lots of stirring, would this not work? Maybe acetone as a co-solvent?
[Edited on 29-10-2008 by bobpage]
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Nicodem
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Tartaric acid is a secondary alcohol and thus can also be substrate to the oxidation. Citric acid is also not particularly resistant to oxidation
regardless of it being a tertiary alcohol (it can be decarboxylatively oxidized). You can use NaHSO4*H2O as an OTC acid buffer but you will also need
an inert cosolvent like acetonitrile (acetone is not particularly suitable as it also reacts with HClO and Cl2, though considerably slower than
secondary alcohols).
You can try one of the several methods using trichloroisocianuric acid (TCCA) for the oxidation of secondary alcohols. There are plenty available and
though most are TEMPO catalysed, there are some direct ones. The direct ones are much less chemoselective as consequence, but this is not important
given you want to use borneol as the substrate. Here is one example (copy/paste from Chem. Abstr. CA 53:29282):
| Quote: | Steroids. XVII. The oxidation of hydroxysteroids with isocyanuric chloride. Mukawa, Fumikazu. Tokyo Metropolitan Univ., Nippon Kagaku Zasshi
(1957), 78 450-2. CODEN: NPKZAZ ISSN: 0369-5387. Journal language unavailable. CAN 53:29282 AN 1959:29282 CAPLUS
Abstract
cf. C.A. 51, 5103f; 52, 20247f. Borneol (I) or isoborneol (II) (0.5 g.), 0.2 g. isocyanuric chloride (III), 50 cc. C6H6, and 0.1 g. pyridine was
heated on a water bath 5 min., poured into H2O, and extd. with Et2O giving 0.4 g. camphor (IV). When N-chlorosuccinimide was used for the oxidation 1
hr. or 20 min., heating was necessary to obtain over 90% IV from I and II, resp. Heating 0.5 g. cholestan-3.beta.-ol (V), 20 cc. C6H6, 0.3 g.
pyridine, and 0.1 g. III 10 min. gave cholestan-3-one. Treating the same amts. of V and III in tert-BuOH gave a halogen contg. ketone, m. 172-5,
which was probably 2.alpha.-chlorocholestan-3-one. Oxidation of chenodeoxycholic acid and cholic acid (VI) with III in C6H6 gave 3,7-dioxocholanic
acid and dehydrocholic acid, resp. To 0.3 g. VI and 20 cc. 0.5% NaHCO3 in Me2CO 50 mg. III was added at 20 and the mixt. allowed to stand at 20 20
hrs., acidified, extd. with Et2O, the Et2O evapd., and the oxo group reduced by heating with 0.5 g. 80% N2H4.H2O, 5 cc. diethylene glycol, and 0.5 g.
KOH; acidifying, filtering, dissolving in EtOH, evapg., and adding 10 cc. Et2O gave 0.15 g. deoxycholic acid etherate, m. 145 and 168-72. Heating 15
min. or allowing to stand 20 hrs. 0.1 g. cholestane-3.beta.,5-diol, 50 mg. III, 50 mg. pyridine, and 10 cc. tert-BuOH gave 5-hydroxycholestan-3-one
(VII), which gave 2,4-dinitrophenylhydrazone of 4-cholesten-3-one. Using Me2CO instead of tert-BuOH and allowing to stand at 25 100 hrs. gave rather
impure VII. Heating 0.3 g. cholestane3.beta.,6.beta.-diol, 0.15 g. III, 0.15 g. pyridine, and 20 cc. C6H6 10 min. gave 75% cholestane-3,6-dione.
Similarly, cholestane-3.beta.,5,6.beta.-triol (VIII) and 5-Me ether of VIII gave 80% 6-oxocholestane-3.beta.,5-diol (IX) and 71%
5-methoxy-6-oxocholestan-3.beta.-ol (X), .nu. 3370-3420 and 1719 cm.-1, m. 139-41, resp., while 5-chlorocholestane-3.beta.,6.beta.-diol,
5-bromocholestane-3.beta.,6.beta.-diol, and 5-methylcholestane-3.beta.,6.beta.-diol were not affected by III. 2,4-Dinitrophenylhydrazone of X m.
165-8 (decompn.).
The difference in the reaction was explained by the steric effect. III with cholesterol .alpha.-oxide gave 21% IX. The oxidation power of III is
higher than that of N-bromosuccinimide. |
Check also:
Hiegel, G. A.; Chaharmohal, A. K. The TCICA test for distinguishing primary and secondary alcohols. J. Chem. Educ., 74, 1997, 423.
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not_important
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Use boric acid, consider it monobasic for this application. Carbon dioxide works as well.
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bobpage
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Thanks guys! How about phosphoric acid?
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smuv
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Thanks nicodem for that J. Chem. Ed. reference.
I am fairly certain this test would also work in methanol in place of acetonitrile. Of note, in methanol at least, TCCA quickly gives a cyanuric acid
precip. with amides that it can N chlorinate; so watch out for misleading results.
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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bobpage
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Won't methanol undergo oxidation as well? Or even a haloform reaction?
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Baphomet
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Regarding phosphoric acid, it can be deprotonated more than once and it's pKa is lower than acetic acid's (see http://en.wikipedia.org/wiki/Acid_dissociation_constant)
For the reaction to avoid creating Cl2, you want the pH to remain above 6.. only very slightly acidic. This is why not_important said to use boric
acid.
It's also why acetic acid is safe even though it is used in copious amounts for the reference you quoted.
[Edited on 29-10-2008 by Baphomet]
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Nicodem
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Bobpage, try dissolving borneol and TCCA (you can buy it in any store with pool chemicals) in acetone. Use a slight excess of TCCA over the reaction
stoichiometry (for example 6 mmol borneol with 2.5 mmol TCCA). TCCA easily O-chlorinates alcohols (this can even be used preparatively, see
FR2625497). The O-chlorinated alcohols (organic hypochlorites) are extremely unstable (particularly those of sec-alcohols) and decompose in the
presence of light to ketones and HCl. So all you have to do is leave the solution of borneol and TCCA in acetone on light until all cyanuric acid
precipitates. Dilute with aqueous NaHCO3 and steam distil the camphor. This way you can avoid all non-OTC reagents, still use the hypochlorite
oxidation method, and do some new chemistry.
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Baphomet
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That sounds like a good synthesis. I might try it myself!
Interesting that you mention the o-chlorinated alkyls. I believe it's the same intermediate that is formed when using the bleach route.
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smuv
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| Quote: | Originally posted by bobpage
Won't methanol undergo oxidation as well? Or even a haloform reaction? |
Solutions of TCCA in methanol are stable at least if prepared before use; I know nothing of long term storage. Methanol cannot undergo the haloform
reaction because it has no alpha hydrogen...or carbon... The haloform reaction is irrelevant though under acidic conditions.
EDIT: Very old texts may say methanol undergoes the haloform, this is because methanol used to always be contaminated with some acetone because of the
manufacturing process (dry distillation).
[Edited on 10-29-2008 by smuv]
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Nicodem
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Solutions of TCCA in methanol are not particularly stable. Just try it yourself. Put one on light and one in the dark and see how much it takes for
the temperature to rise and/or cyanuric acid to precipitate. It can take minutes or days, depending on the conditions. Never trust that a solution is
stable just because it was used in some published procedure and on a small scale. Such solutions that decay autocatalyticaly and/or exothermaly can be
source or big troubles on a scale larger than just few millilitres. For example, a solution of bromine in methanol (or even worse, in ethanol!) or NBS
in THF can be used on a small scale if used within a minute or two and kept cold/dark but as soon as you want to use a larger volume of such unstable
solutions you are asking for troubles as these can just boil over in matter of seconds once the reaction kicks in.
| Quote: | Originally posted by Baphomet
Interesting that you mention the o-chlorinated alkyls. I believe it's the same intermediate that is formed when using the bleach route.
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Indeed, this is the "bleach route", just using TCCA as source of Cl(I) species rather than the calcium hypochlorite. The mechanism is the same. (As a
side note, beware of the nomenclature rules: The small "o-" as you use it stands for ortho rather than indicating the oxygen
heteroatomic position in alcohols for which a capital italic O must be used.)
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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smuv
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| Quote: | | Solutions of TCCA in methanol are not particularly stable. |
I did try this very thing a few weeks ago to see if a reaction proceeded through a methyl hypochlorite intermediate. In a test tube I dissolved a
large quantity of TCCA in methanol, and let it sit; A few hours later I checked it and noticed no precipitate. I believe though that if I left the
solution for a very long time I would eventually get a precipitate.
Do you have personal experience with solutions of TCCA in MeOH or are you just going by logic?
"Titanium tetrachloride…You sly temptress." --Walter Bishop
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Nicodem
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I have experience with TCCA in methanol as reaction solvent where the redox reaction occurs on the more reactive substrate. There are no troubles
using methanol, ethanol or other alcohols as solvents in reactions with TCCA except for them to get involved in the reaction as nucleophiles but that
is usually the point in using them (like in chloromethoxylations, etc.). I just checked now on 500mg TCCA in 10ml methanol and indeed the cyanuric
acid only starts precipitating after heating to boil. Yet, I have seen more complex secondary alcohol substrates oxidized in mater of less than an
hour at room temperature in a reaction with TCCA, thus I would never consider alcohols, not even primary ones, as inert solvents toward TCCA. It is
however true that methyl hypochlorite solutions are relatively stable if kept away from light, so that I would expect a solution of TCCA in methanol
would not form any precipitate for days or more at room temperature in the dark, but I would not be so sure about its stability on sunlight. I have
seen what happens to the before mentioned solutions of Br2 in ethanol or NBS in THF, so I treat all these oxidant/fuel mixtures with great care. It is
quite scary when a solution in a beaker all of a sudden starts boiling uncontrollably, splashing around, and there is just about nothing you can do.
As an example known to many members here, acetone solutions of TCCA are quite stable, but once you add the tiniest amount of a strong acid they will
just boil off like crazy at the least expected moment. That's why I would rather suggest using acetonitrile or ethyl acetate instead of acetone for
the discussed oxidation of borneol, but unfortunately they are less available solvents for the average amateur when compared to acetone.
t-Butanol should be completely inert toward TCCA, if an alcohol has to be used, since t-BuOCl is quite stable and can actually be
distilled and purified.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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smuv
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I was getting at using MeOH for the functional group test you posted as acetonitrile is something I have to order (instead of available at any gas
station).
After doing acid catalyzed oxidations of both acetone and ethanol with TCCA, I agree, these solutions should be treated as loaded guns.
[Edited on 10-29-2008 by smuv]
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Baphomet
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There is an American patent related to the method specified by Nicodem:
http://www.patentstorm.us/patents/5821374/fulltext.html
Interesting in that they use sodium acetate (in addition to the ever-popular TEMPO), presumably the NaCH2COOH is a buffer?
TCCA can swap each Cl for one H on the target, taking some acidity out, the other acidic byproduct would be hypochlorous acid which I would not have
thought would require buffering (pKa = 7.5)
Maybe the reaction is smoother with the salt, possibly even sodium bicarbonate would suffice. Another thing to try is to leave the vessel in a
refrigerator or freezer and stir occasionally. The bleach methods seem to run fine in the cold.
[Edited on 1-11-2008 by Baphomet]
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Baphomet
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Oops, the byproduct would be HCl. That explains the buffering then..
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bobpage
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What happens if it's not buffered? the reaction described above did not have any base..
Won't NaHCO3 react with Cl- to produce NaCl + H2O + CO2? If it does that could affect the oxidation by removing Cl when we only want to remove H..
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not_important
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| Quote: | Originally posted by bobpage
Won't NaHCO3 react with Cl- to produce NaCl + H2O + CO2? If it does that could affect the oxidation by removing Cl when we only want to remove H..
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Try balancing that, as is you're short a H and lose an electron. Bicarbonate will liberate HOCl from NaOCl, but doesn't do anything to Cl(-) (as you
wrote).
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bobpage
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So the bicarbonate should be a good buffer for this system then? (Aside from solubility issues)
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Klute
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Not using any buffer will liberate HCl, which reacts with unrecated TCCA to form Cl2. These conditions are too harsh for most priamry alcohols or
activated arenes, but should work for secondary alcohols.
The sodium acetate should be used to capture the liberated HCl, but it forms a very thick slurry, requiring huge amounts of solvents.
Usually, TCCA is sued so than HOCl in formed in minute amounts, it seems to be a more smoother/selective oxidant than OCl-. But NaOCl solution are
often used with TEMPO and primary alcohols to aldehydes, most of the time in a biphasic system. NaOCL alone is very rarely used with primary alcohols
without TEMPO or a non-polar solvent.
I think NaHCO3 could be used with TCCA, HOCl pka is 7.54, HCO3-/H2CO3 is 6.5
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Nicodem
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| Quote: | Originally posted by bobpage
So the bicarbonate should be a good buffer for this system then? (Aside from solubility issues) |
The TEMPO catalysed oxidation of alcohols has a completely different mechanism from the oxidation using HClO. In the TEMPO mediated oxidation
hypochlorites or N-chloroamides (often in the presence of bromides) only serve to reoxidize the catalyst and not as the actual oxidants for
the alcohol. The TEMPO based reaction requires basic medium, hence the buffering with NaHCO3. The hypochlorite based reaction requires acidic media
since this favours the formation of hypochlorite ester intermediates. These reactions are mechanistically completely different and have absolutely
nothing in common, so make sure you don't confuse them.
In the oxidation of borneol with hypochlorites/acid or TCCA, an equivalent of HCl forms and thus the reaction is autocatalytic. This HCl does not
cause much troubles since camphor is not so easily alpha-chlorinated. If you use acetone as solvent, some of it will undoubtedly get chlorinated, so
make sure you do this on a really small scale and quench the reaction with saturated bicarbonate before you steam distil the product (chloroacetone is
a nasty lacrymatory compound).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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scientician
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Wow, this is a really old thread!  Sorry for the resurrection; I have full
online journal article access through my master's program and this goddamn thread is the best info on the net I can find regarding this particular
reaction. Go figure.
I've been attempting this reaction for a long time on cholesterol, always getting an unidentifiable sticky white tar with gobs of precipitated
substrate in it. It has the consistency of dry tree sap and is soluble in nothing but concentrated hydrochloric acid. Having to clean it out of my
glassware after a failed reaction was almost too much post-humiliation insult for me to bear.
Not being able to obtain GAA easily, I have tried multiple organic acids in an attempt to generate hypochlorous acid in situ. Early terrible results
included no acid (thought the GAA was there only as a solvent,) household vinegar (brought the cholesterol out of sol. in acetone + tar,) citric acid
(water-soluble tar) and last night per the advice on this thread I used boric acid.
I litmus tested the 6% bleach (0.87M) before and after the equimolar addition of boric acid. No change was observed in the color of the litmus paper
(estimated the pH to be ~6.5.) Adding an additional 0.5 molar equivalent did not change this result. Proceeding with the reaction yielded results
slightly better than citric acid, but by no means was there an absence of TAR!
In a blind rage now I decided to acidify the equimolar bleach/boric acid solution with oxalic acid. I tested 20ml of the solution against .5 grams of
oxalic acid dihydrate in a stoppered 500ml boiling flask. The result both aroused and terrified me. It gave off a non-colored gas that resembled the
behavior of club soda. This caused the pH to go to ~5.5.
My knee jerk assumption was that I had produced a small amount of chlorine gas, but I wonder if I didn't make carbon dioxide by converting the oxalic
acid to it's conjugate base, which in turn couldn't conjugate with the sodium ions in the solution due to the presence of the boric acid. If this
is right, the reaction should be successful and would still retain it's "greenness" because the most toxic thingy, the oxalic acid, leaves the
reaction as harmless carbon dioxide, thus saving the whales.
So I'm going to go run this bitch right now to see what happens.  If it doesn't
work then I'll just figure out how to get some GAA.
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scientician
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Did my reaction, and near as I can tell without NMR analysis, it worked. No tar formed, and I have ran this reaction several times.
I did some digging into the reaction between NaOCl and oxalic acid and couldn't find anything. I figured the reaction would be similar to H2O2/oxalic
acid without the boric acid competing for the sodium ions. This study indicates oxalic acid will indeed decompose into CO2 under the right
conditions:
http://www.ornl.gov/info/reports/1981/3445605762877.pdf
Once I add the oxalic acid to the boric acid/NaOCl solution, the oxalic acid is deprotonated, and the Na+ ions are scavenged away by
tetrahydroxyborate- ions. The result is sodium tetrahydroxyborate and hypochlorous acid.
It is important to realize that the amount of oxalic acid required for this is extremely low, I have had success so far with as little as 1% mole
ratio oxalic acid to bleach/boric acid. Additionally, I added the oxalic acid right before the reaction, or just included it with my solvent and
substrate (cholesterol purified from egg yolk and acetone.)
The only complication I'm having now is a white precipitate which I'm fairly certain is just boric acid crystals. If anyone knows any better please
let me know.
TL,DR version. Equimolar boric acid by itself is an okay replacement for GAA. Boric acid and 1% mol equivalent oxalic acid appears to be a great
replacement for GAA.
[Edited on 4-5-2011 by scientician]
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