Author Topic: alkylation of quinones  (Read 21697 times)

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Antoncho

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The mechanism
« Reply #60 on: December 10, 2003, 07:18:00 AM »
I bet the mechanism is pretty similar to the one described in

Post 267698

(Antoncho: "P-MeO-phenol from hydroquinone: part II", Novel Discourse)
for p-benzoquinone - thru hemiacetal which is instantly reduced with SnCl2

Note that in our case the major product is the dimethylated compound - which in the HQ case is present only in trace qtties. Obviously it is the dimethylhemyacetal that is reduced, but i have no clue why. Maybee di/mono methylhemiacetal equilibrium is connected to concentration of the quinone (in the HQ patent they got diMeObenzene only when employing larger qtty of benzoquinone catalyst).

In any case, it seems to me that SnCl2 needs not bee unhydrous at all (naturally, with dihydrate one wouldn't see any exoterm as in Shulgin's report) since its only purpose is to reduce.




Antoncho

azole

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Re: Mechanism???
« Reply #61 on: December 10, 2003, 12:51:00 PM »
If this is the case, then might it be possible to just dissolve hydroquinone in MeOH, add some lewis acid (perhaps ZnCl2??), then gas with anhydrous HCl? Seems like that could work on any phenol.
   There is something special about naphthols: they tautomerize easily into the corresponding ketones without complete loss of aromaticity. That's why both 1- and 2-naphthols form ethers (reversibly) when heated in alcohols in the presence of an acidic catalyst. The reaction was applied mainly for the manufacture of 2-ethoxynaphthalene (neroline) and 2-methoxynaphthalene (yara yara) which were used in perfumery.

Antoncho

  • Guest
So....
« Reply #62 on: December 10, 2003, 03:37:00 PM »
...so, THAT's why in case of napthamethoxyphenol the reaction proceeds all the way to the diMeO compound...

Which would probably mean that it won't work for benzene nucleus-based things.

azole

  • Guest
exception
« Reply #63 on: December 10, 2003, 06:11:00 PM »
...so, THAT's why in case of napthamethoxyphenol the reaction proceeds all the way to the diMeO compound...

   Exactly.

Which would probably mean that it won't work for benzene nucleus-based things.

   Phloroglucinol is an exception. It reacts (via keto tautomer) with methanolic acids (HCl [1,2] or H2SO4 [3]) to form mainly phloroglucinol dimethyl ether, which can be further methylated with MeI/KOH [1] or with Me2SO4/KOH [2,3] to 1,3,5-trimethoxybenzene.
   Direct methylation of phloroglucinol with MeX is impossible because C-methylation prevails.

1. W. Will, Ber., 21, 602-616 (1888).
2. K. Freudenberg, Ber., 53, 1416-1427 (1920).
3.

http://www.erowid.org/library/books_online/pihkal/pihkal162.shtml



More references can be found in Weygand - Hilgetag, p.331 (Russian translation).

moo

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Interesting... phloroglucinol dimethyl ether...
« Reply #64 on: December 10, 2003, 07:53:00 PM »
Interesting... phloroglucinol dimethyl ether could be ortho-formylated and the product methylated to 2,4,6-trimethoxybenzaldehyde.


Chimimanie

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convenient procedure for allylation of quinone
« Reply #65 on: December 18, 2003, 03:38:00 AM »
This procedure is very suited to our needs, it was more tuned up than the former

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890

poix posted all above this thread. Both procedure use the same silver/persulfate to generate Ag2+ in situ which oxyde a suitable alkyl chain to form a radical that will get quenched by the quinone. There are two notable differences here against the former:

-first: the alkyl chain is not an acid which loss CO2 to generate the alkyl radical minus one C based on the acid (ex: butyric -> CH3CH2CH2. ) , but an ester of oxalic acid, which come from an alcohol with the same number of carbon than the alkyl chain to bee put in place. The oxalate is oxydatively hydrolised and generate a R. radical, where the former OH was, which will react with the quinone.

-second: here they solve the problem of poly alkylation of the quinone by various radicals by using a two phases mixture. This can bee used in the old orgsyn.org ref too, if you want to start with the acid in place of the oxalate. Higher yield and purity are achieved through such reaction medium change.

The true problem now is synthetising the allyl oxalate, as I said in another thread, it can bee done by transesterification of oxalate diethyl ester, then basic hydrolyse of one of the allyl ester to the free acid. Sadly the patents are in Japanese. Refs to make this allyl oxalate are highly wanted. Well, at worst using some proper acid (like N-acetyl beta-alanine or the acetal of acetoacetic acid) and this biphasic medium in place of the one phase of orgsyn ref will give rise to better yields and next to zero polyalkylation of the quinones. The convenience of this route gained a few points here, bees.  ;)

Check the table: 96% for the allylation of quinone! Yeesh!  8)  

Here is the gem:

A New Selective Method for the Homolytic Alkylation and Carboxylation of Quinones by Monoesters of Oxalic Acid Fausta COPPA, Francesca FONTANA, Edoardo LAZZARINI, and Francesco MINISCI Chem. lett. 1992 7 1299

Abstract:

Alkyl and alkoxycarbonyl radicals were generated by oxidative decarboxylation of oxalic acid monoesters by persulfate; they were then utilized for the selective substitution of quinones.

The oxidative decarboxylation of oxalic acid monoesters proved to be a very effective source of alkoxycarbonyl and alkyl radicals, useful for selective syntheses. The alkylation of heteroaromatic bases was described in the preceding Letter [1] and in a recent report [2] of a more expensive and less effective procedure.

Now we report how this radical source can be successfully utilized for the selective alkylation (Eq.1) or carboxylation (Eq.2) of quinones in a two-phase system. The results are shown in Table 1. With esters of tertiary or secondary alcohols, alkylation (Eq.1) mainly occurs, whereas with primary alcohols carboxylation (Eq.2) becomes the main process. With esters of allylic alcohols only allylation occurs and we expect a similar behaviour with esters of benzylic alcohols.



Operating in a two-phase system, constituted by water and an organic solvent, such as CH2Cl2 or benzene, is particularly important for minimizing polysubstitution, because the reaction products are generally more lipophilic than the starting quinones and are therefore preferentially extracted by the organic solvent, whereas the substitution reaction takes place in the aqueous phase. With quinones of very low solubility in water, such as the naphthoquinone derivatives, using two-phase system constituted by three solvents (CH2Cl2, CH3CN, and H20) improves the effectiveness of the reaction.



The mechanism of the reaction involves the following steps:

i) generation of the carbon-centered radicals (Eqs.3-5)



ii) addition to the quinone ring (Eq.6)



iii) oxidation of the radical adduct in a redox chain (Eq.7)



It is noteworthy that when alkoxycarbonylation (Eq.2) is the prevailing reaction, as in the case of the reaction between benzoquinone and ethyl monoester, a minor amount of 2,6-diethoxycarbonylhydroquinone is formed. We explain this result by the fact that the introduction of an alkoxycarbonyl radical, instead of an alkyl radical, on the quinone ring increases the redox potential of the resulting phenoxy radical and makes its oxidation by persulfate slower (Eq.7). This allows to reach stationary concentration of the phenoxy radical, suitable for acting as scavenger towards another alkoxycarbonyl radical (Eq.7b).

Considering that the reaction takes place in the aqueous phase, in which the solubility of the quinone is generally very low, that the ethyl radical is not formed in siqnificant amount and that the rate is given by the expression r = k [-COOR] [quinone], it follows that the rate constant for the addition of the ethoxycarbonyl radical to the quinone ring must be high (>10^6 M-1 s-1). The lower solubility of naphthoquinone explains its lower degree of alkoxycarbonylation compared to benzoquinone under identical reaction conditions.

A general experimental procedure is given:

A solution of 10 mmol of monoester of oxalic acid and 5 mmol of quinone in 20 ml of the solvents reported in the Table was added to 20 ml of an aqueous solution containing 10 mmol of Na2S208 and 0.5 mmol of AgN03. The mixture was refluxed for 2 h, then the organic layer was separated, dried and analyzed by GC and GC/MS. The reaction products were isolated by flash-chromatography on silica gel and identified by comparison with authentic samples.[3] This is the first example, to the best of our knowledge, where the homolytic carboxylation, of quinones is achieved. On the other hand, the above described alkylation represents the only procedure so far known for the radical alkylation of quinones by alcohols, whereas alkylation by carboxylic acids has been reported by several groups.[4]

References:

[1] F. Coppa, F. Fontana, E. Lazzarini, F. Minisci, and L. Zhao, Chem.Lett., preceding paper.
[2] H. Togo, M. Aoki, and M. Yokoyama, Chem.Lett., 1991, 1691.
[3] F. Coppa, F. Fontana, F. Minisci, M. C. Nogueira Barbosa, and E. Vismara, Tetrahedron, 47, 7343 (1991) and references therein.
[4] Ref.3; D. H. R. Barton, D. Bridan, and S. Z. Zard, Tetrahedron, 43, 5307 (1987); B. Lin, L. Gu, and J. Zhang, Rec.Trav.Chim.Pays-Bas, 110, 104 (1991) and references therein.

Nicodem

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Just wanted to remember all that the ...
« Reply #66 on: December 19, 2003, 11:25:00 AM »
Just wanted to remember all that the phtalimido protection would be the most obvious choice for two reasons:

1. The phtalimido-2C-H can be either chlorinated, brominated and especially iodinated with elemental halogens without any troubles. It is very stabile in basic as well as acidic conditions. Besides it gives no wary of sidereactions during the dimethylation with DMS or MeI. The other amides might interact with radicals (if it is a radical mechanism) because of the amide hydrogen.

2. Most importantly the phtalimido-beta-alanine is accesible trough the Michael addition of the potassium phtalimide to the acrylic acid (or crotonic acid if you are up to the 2,5-diMeO-amphetamines):

CH2=CR-COOH + C6H4(CO)2NK  --> C6H4(CO)2N-CH2-CHR-COOH

Where R is H or Me.
To my opinion there is no other simplier route to a perfectly protected beta-alanine and it can be done in a water solution. Besides acrylic and crotonic acids are so cheap.

Edit: Maybe I was to fast with that reaction above. There is a similar synth of beta-amino-alanine in the Organikum in the chapter 7.4.4. (6th edition). It uses acrylonitrile as a starting material and the nitrile is then hydrolised together with the phtalimido protection. There is no statement why acrylonitrile is used and nothing is said that it would not work on acrylic acid (or its ester). I have set a test reaction with acrylic acid and will report on the results.


Nicodem

  • Guest
Preparation of phtalimido-beta-alanine
« Reply #67 on: December 20, 2003, 09:21:00 PM »
Since this is an ancient tread I have to remember those that don't have the time to go trough all of it that the most ingenious idea that it contains somewhere is to alkylate benzoquinone with the

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0890

procedure forming directly a protected ethylamine or isopropylamine side chain, and then addition of HX followed with the methylation of the hydroquinone product, deprotection and voila, you have your 2C-X or DOX. For this we need phtalimido-beta-alanine.

Here are the results of the test reaction mentioned in the previous post for the...

Preparation of phtalimido-beta-alanine













Molecule:

the reaction scheme ("c21ccccc1C(NC2=O)=O.C=CC(=O)O>>C(CC(=O)O)N2C(c1ccccc1C2=O)=O")



In a 50ml flask there was added 0.8g of sodium hydroxide (20mmol) in 10ml of water (note 1), 1g of phtalimide (6.8mmol) and 1ml of acrylic acid (13.6mmol). This was set to reflux for 9h and then left at room temperature over night (note 2). The next day (today) the clear and only slightly yellow solution was slowly acidified with 12ml of 10% hydrochloric acid and after a minute of stirring beautiful, microscopic needle-like crystals started to grow. The product was collected by suction filtration after being cooled on an ice bath and was washed three times with ~10ml of cold water. It was then left to dry on air. 0.98g of colorless crystalline product was obtained (66%).

To test the identity of the product a heating experiment was performed (sorry, but I don’t have a microscope to determine the melting point). I put a few mg of the product as well as phtalimide ~2cm from each other on a flat glass on a hot plate. I covered it with a round glass and begun heating. The phtalimide slowly sublimated on the upper glass while the product remained unchanged all the time. Only after all of the phtalimide already condensed on the upper glass the product started decomposing slowly without any visible melt or sublimation. The only other compound that I think could be a product is phtalic acid, but it decomposes to phtalanhidride at about 205°C and this also readily sublimates. Phtalic acid is also relatively more soluble in water than the product. If some was formed it would probably not crystallize out after the acidification and water washings. If there are no reasonable objections I’ll conclude that the product is quite probably the desired phtalimido-beta-alanine.

Note 1: This might have been too much of sodium hydroxyde. After the ftalimide gets consumed in the reaction the mixture gets more basic and this might cause some hydrolysis of the phtalimides, therefore lowering the yield and producing phtalic acid as a byproduct. I would use less hydroxide the next time or maybe change it with the less nucleophilic and less basic carbonate.
Note 2: Some bigger chunks of phtalimide took an hour or more of reflux to dissolve completely. For some unrelated reasons I had to stop the heating for half an hour during the beginning of the reflux and I observed that the phtalimide salt had precipitated on cooling. So it seems the sodium hydroxide would be better substituted with potassium hydroxide or carbonate since the potassium phtalimide should be more soluble in water. Anyway it is interesting to note that after 9 hours of reflux no precipitate formed on cooling indicating that most of the phtalimide got consumed.

To bad I don’t have any ammonium peroxydisulfate to check this alkylation of benzoquinone. Somebody else will have to continue from here on  :P .


Rhodium

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Synthesis of N,N-phthaloyl-beta-alanine
« Reply #68 on: December 21, 2003, 12:45:00 AM »
Synthesis of N,N-phthaloyl-beta-alanine
Arch. Pharm. 334, 323–331 (2001)

74 g (0.5 mol) of phthalic acid anhydride and 0.5 mol of beta-alanine (3-aminopropionic acid) were refluxed in 300 ml toluene in the presence of 6.5 ml triethylamine for 2 h in a Dean-Stark apparatus. The organic solvents were removed in vacuo, 700 ml of water and 10 ml of concentrated HCl were added and the mixture stirred for 30 minutes, filtered, and dried. Recrystallization from ethanol yielded 3-phthalimidopropionic acid, 99.9 g, 91%, mp 151–152°C.


Alternative prep from beta-alanine and phthalic acid (96% yield): Nucleosides & Nucleotides 17(9-11), 2021-2026 (1998)


Chimimanie

  • Guest
Obviously its easier
« Reply #69 on: December 21, 2003, 05:11:00 AM »
Good suggestions Nicodem!  :)

True obviously the phtalimide is a far nicer protecting group than the acetyl here:
-the preparation is easier, quick and doesn't require listed precursors (like acetic anhydride).
-the removal is better yielding than the hydrolyse of the acetamide.
-maybe you are right and the fact there are no free H on the azote is good, but I dont think that is important, a H on an amide is not labile (i know this is radical chemistry but heh).

I searched some data on the phthalimido-b-alanine and its methylated congener:

The solubility of phthalimido-b-alanine in water (calculated) range from sparingly soluble at pH 1, to very soluble above pH 7, and slightly soluble at pH4. So it look ok for this reaction. Its melting point is 150-151°C.

The solubility is more or less the same for the methylated one (from 3-amino butyric acid), the melting point of this chemical is more disparate tough: ~105°C or ~120°C, recrystallized from H2O or benzene.

Finally I have a synth again for the protected beta-alanine, from

Patent US4849436

, example 12:

Preparation of N-phthalyl-b-alanine:

A mixture of 89.09 g (1.0 mol) of beta-alanine and 148.12 g (1.0 mol) of phtallic anhydride was stirred at 180-190°C for 30 minutes. Upon adding water, a solid formed which was filtered, washed with water, and recrystallized in ethanol/water to give 178.0g of a white powder, mp 152-153°C.


I hope the phtalimide moiety will resist the harch oxydative condition it will bee subjected here, but I think it should work well.

HQ -> BQ -> BQ-ethyl-2-phtalimide -> *insert halogenation here maybe* -> HQ-ethyl-2-phtalimide -> 2C-H (X) phtalimide --*or halogenation here maybe*--> 2C-H (X) -> 2C-X

6 steps from hydroquinone, its ok, especially since the deprotection is better, the phtalimide is easier to synth, and the two phase medium is higher yielding.  I think this route is officially convenient now, lets practice it!  ;)

Nicodem

  • Guest
You got me confused
« Reply #70 on: December 21, 2003, 12:19:00 PM »
Rhodium: Is that beta-alanine they used? It is written alanine, but the product is 3-phthalimidopropionic acid (a typo ?). But if its m.p. is 151°C I don't know what the hell I got out of the reaction (phtalimide has a m.p. of 238°C and phtalanhidride 131°C). I can only see the 1,4-addition on the acrylic acid possible here even though it immensely bothers me why I can't find a reasonable explanation on why acrylonitrile is used for the synth of beta-alanine. I would prefer getting the 3-phthalimidopropionic acid directly as the nitrile hydrolysis can't effectively be done without phtalimide deprotection, right? I'll try to make an IR of the product in the next few days if I'll have the opportunity and solve this mystery.

Chimimanie: You may be right. The amide hydrogen probably does not interfere, but I'm not 100% sure. The radicals abstract hydrogen atoms if there is a possibility of forming a more stable radical. I don't have any tables of radical's stability/energies at hand but I can tell you that the primary C-radical that forms in the proposed reaction is the least stable possible and therefore the more prone to side reactions. Actually I would not be surprised if it would rearrange to form the secondary radical that would be highly stabile (also because of the phtalimide nitrogen). This would be a big disappointment, as it would yield the alpha-phenylethylamines.
I count on the hope that the primary radicals would react faster than they would rearrange (I just hope they are not completely unselective as the phtaloyl ring is also a possible substrate even though many magnitudes less reactive than BQ). For example, in the table I of Org. Synth. procedure, all the acids have a substituent at the alpha-position that stabilizes the formed radical (PhO, t-Bu, Cl...) with the exception of adipic acid. Without this exception I would consider our reaction impossible.
I also think that it would be worth trying the nucleophilic addition on the BQ-CH2-CH2-Phtaloyl. If doing an addition of, for example, HBr in as anhydrous condition as possible the phtaloyl protection would probably resist and the major product would (again) probably be the 4 and 5-Br substituted HQ-CH2-CH2-Phtaloyl. Therefore avoiding both the reduction of BQ and the halogenation in the last step.


Rhodium

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beta-alanine (3-aminopropionic acid)
« Reply #71 on: December 21, 2003, 04:32:00 PM »
Is that beta-alanine they used? It is written alanine, but the product is 3-phthalimidopropionic acid (a typo?).

They used beta-alanine (3-aminopropionic acid) in both syntheses, the greek symbol didn't carry over when I did my copy-paste thing and then I forgot to add it again. I have now edited my post.

I would prefer getting the 3-phthalimidopropionic acid directly as the nitrile hydrolysis can't effectively be done without phtalimide deprotection, right?

That is indeed possible, I have seen that transformation being done in one of the articles I went through searching for the above preps. Want me to re-retrieve it?


Nicodem

  • Guest
That is indeed possible, I have seen that...
« Reply #72 on: December 21, 2003, 08:33:00 PM »
That is indeed possible, I have seen that transformation being done in one of the articles I went through searching for the above preps. Want me to re-retrieve it?

I’m glad its possible and I hope it is an easy preparation. Unfortunately I don’t have any acrylonitrile. By the time I’ll get that and the peroxydisulphate I’ll be able to retrieve that paper by myself. Thanx anyway, maybe if someone else is interested?


Rhodium

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Reductive Methylation of Quinones
« Reply #73 on: June 16, 2004, 12:54:00 AM »
Reductive Methylation of Quinones
J. Gripenberg & T. Hase

Acta Chem. Scand. 17, 2250-2252 (1963)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/quinone.reductive.methylation.html)

Abstract
A reductive methylation of quinones using dimethyl sulfate in the presence of pyridine is described. It is probable that methylpyridinium hydroxide, formed in the reaction, is the actual reductant.

This article has been referenced in

Post 265551

(foxy2: "Re: alkylation of quinones", Novel Discourse)



GC_MS

  • Guest
1,4-cyclohexanedione
« Reply #74 on: June 22, 2004, 09:28:00 AM »
The recently posted article by Rh somewhat caught my attentions:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/2-alkyl-hydroquinones.html



1.4-Cyclohexanedione is commercially available, but not very cheap. But some literature browsing gives a few good alternatives to synthesize this in the lab.

However, I was thinking a bit further about the possibilities of using 1.4-cyclohexanedione as precursor for p-benzenediol derivatives. The aforementioned article only used (substituted) benzaldehydes and aliphatic aldehydes to furnish the corresponding 2-alkyl-1.4-dihydroxybenzene. However, I was wondering about the possibility to use glyoxilic acid and/or pyruvaldehyde. Theoretically, glyoxilic acid yields 2.5-dihydroxyphenylacetic acid, and pyruvaldehyde would give 2.5-dihydroxyphenylacetone.

However, I see the theoretical possibility for both compounds to form other, (possibly) not targeted compounds as well (maybe the ?-keto functional group of pyruvaldehyde may condense with 1.4-cyclohexanedione as a competing reaction, or maybe there won't be any reaction at all...).

However, if the reaction between 1.4-cyclohexanedione and pyruvaldehyde would yield 2.5-dihydroxyphenylacetone, that would be very nice  8) . Pyruvaldehyde is widely used as food additive.

Ideas? Input? Comments?


Nicodem

  • Guest
Looks good
« Reply #75 on: June 22, 2004, 03:40:00 PM »
That reaction has been echoing in my mind since I first saw a reference to that Green Chem paper in a microwave chemistry paper (

https://www.thevespiary.org/rhodium/Rhodium/pdf/microwave.organic.chemistry.review.pdf

; p9240). Unfortunately I have never come across any cyclohexa-1,4-dione since and don’t own a microwave either  :) .
GC, I think your idea of using pyruvaldehyde might just work since aldehydes are generally more elctrophylic than ketones, but I must admit I see no OTC source of this chemical. There are a lot of useful chemicals used as food additives and yet I have no idea how to buy them pure. :(  However I would be very glad to hear your results if you ever end up experimenting with this route. ;)
Since I lately came across some succinic acid I was also thinking of the Org. Synth. procedure for cyclohexa-1,4-dione (

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0288

). The possibility of using the intermediate diethyl 2,5-dioxocyclohexane-1,4-dicarboxylate to alkylate it with something like chloroacetone diethylketal or with allylbromide caught my attention. It might just bee possible to monoalkylate it, hydrolyze/decarboxylate and only then condense it with an aldehyde. For example:



The keto group should not interfere since it is much less reactive than the aldehydes. But even if all these steps would, work which I doubt, it still bothers me which positional isomer would prevail at the last step? I suspect some unbearable number of minor side product separable only with a column. :(

There is one intriguing thing about these two papers as well as the reaction described in

Post 481577 (missing)

(Nicodem: "UV promoted BQ acylation w/aldehydes", Novel Discourse)
. Why, oh, why they never rapport any example with paraformaldehyde? Is formaldehyde not considered an aldehyde or what!?