Sciencemadness Discussion Board

why not haloform reaction results in an α keto acid?

adianadiadi - 1-5-2011 at 09:39

During the haloform reaction, the base hydrolysis of α,α,α-trihalocarbonyl compound gives the haloform as the final product.

But why not the halogen groups are substituted by the OH groups to give a trihydroxy compound which can lose water molecule to give finally an α keto acid?

bbartlog - 1-5-2011 at 12:07

You would want to read about nucleophilic acyl substitution to answer this question. I can't provide you an answer that I am sure is correct but I do believe that understanding this step is the key to the answer.

adianadiadi - 1-5-2011 at 15:34

I feel it is the steric hindrance that plays role and the weak ness of C-C bond. Any idea?

bbartlog - 1-5-2011 at 17:46

But C-C bonds aren't normally weak... if you want to say that *this* one is, well, that just raises the question of why, once more. I also see no role for steric hindrance here.

UnintentionalChaos - 1-5-2011 at 18:55

the halogens are probably not leaving at any appreciable rate for SN1 and SN2 is inhibited by steric bulk of the chlorines, I'd assume. Furthermore, the trichloromethyl group inductively withdraws electron density from the carbonyl making it a better electrophile for attack by OH-. Lastly, CCl3- is not that bad of a leaving group, unlike unsubstituted CH3- would be.

spirocycle - 2-5-2011 at 07:43

1,1-dihydroxy carbons are pretty unstable, so its not a likely intermediate, especially considering the substantial stability of the trihalocarbon

AndersHoveland - 2-5-2011 at 13:38

This is an interesting question, and I do not know the answer.

It would appear that (-)CCl3 is an intermediate species, and that this immediately combines with either a hydrogen ion (even in alkaline solution there is still a very small equilibrium of hydrogen ions), or reacts directly with water. The (-)CCl3 anion quickly decomposes into the dichlorocarbene radical and chloride ion. I do not know whether in the Haloform reaction (-)CCl3 reacts to form chloroform before decomposing, or whether the dichlorocarbene goes on to react to form the final chloroform product. The latter seem unlikely, as one would then expect a much high proportion of CO2 among the products.

Chloroform actually very slowly hydrolyzes with water, which can take months. Refluxing it with an alkaline solution causes much more rapid hydrolysis, around 2 hours. Suffice to say, the C--Cl bond is very slow to react. CHF3 is almost inert toward hydrolysis, whereas bromoform reacts much more rapidly.

[Edited on 2-5-2011 by AndersHoveland]

adianadiadi - 2-5-2011 at 17:34

It is interesting that bromoform reacts rapidly in alkaline medium. Then the yields of bromoform must be less.:)

Ebao-lu - 3-5-2011 at 06:56

yep that is because CCl3- anion is relatively stable an the reaction of chloroform formation is much faster then SN2 substitution of Cl with OH-(due to steric issues mostly, because monohalocarbonyl comp-s in this case react with OH- very fast) .But if you take, say, α,α-dihalocarbonyl compound, the situation would become different - because of less stability of (-)CHHal2, it can not break down into dihalomethane, at the same time - the steric conditions would be better for nucleophilic substitution and you will get, supposedly, diketo carbonyl compound (if either favorski, favorski-like or benzil rearrangement would not take place). It can become a,a-dihydroxycompound only if the hem-diol/ketone equilibrium highly favors for diol formation, like in case of 2 position in some 1,2,3-triones

[Edited on 3-5-2011 by Ebao-lu]

[Edited on 3-5-2011 by Ebao-lu]

[Edited on 3-5-2011 by Ebao-lu]

AndersHoveland - 3-5-2011 at 14:20

"dihalocarbonyl" was probably not the most accurate name to use, as this would imply O=C(X)2, where X is a halogen atom.

The post of "Ebao-lu" is confusing. I will try to translate it into more simple wording. He is saying
that in the intermediate CH3C(=O)CHCl2 molecule, that (-)CHCl2 is not able to ionize off since it is much less stable than (-)CCl3. Cl means a chlorine atom. He claims conditions would be better for substitution, forming something perhaps like CH3C(=O)C(=O)H, if I understand what he was trying to say correctly. He then says that it might be possible that the equilibrium would favor the central carbon atom to have two hydroxy groups (OH)
instead of a (=O). For example, many compounds such as the one in this link, , actually have two hydroxy groups on the same carbon (this would be on central ketone group, although the picture does not show this)

I disagree with "Ebao-lu". Substitution would likely be too slow to be significant during the reaction, except perhaps if the halogen used was iodine (in which case iodine would need to be added into the akaline solution of ethanol or acetone, since hypoiodite quickly disproportionates into iodide and iodate). Instead, my personal view is that a side carbon, with chlorine atoms on it, on a molecule of acetone, becomes oxidized much faster than a carbon with fewer or no chlorine atoms on it.

Acetone has a tautomer CH2=C(OH)CH3. I suspect that the ionization of a H(+) off one of the methyl groups (CH3) is easier if there is one or two chlorine atoms on the methyl group.

Cl2CHC(=O)CH3 <--> H[+] [-]CCl2C(=O)CH3 <--> H[+] CCl2=C(--O[-])CH3 <--> CCl2=C(OH)CH3

While the hydrogen in chloroform HCCl3 is capable of ionizing off, as is evidenced by the reaction between acetone and chloroform in the formation of "chlorobutanol" HOC(CH3)2CCl3, the ionization is probably much easier when there is an adjacent ketone group to withdraw the electron to the oxygen atom.

[Edited on 3-5-2011 by AndersHoveland]

Ebao-lu - 3-5-2011 at 23:48

yes, you understood my post correctly.
the only thing, is that i did not meat that 2,2-dichlorocarbonyl compound can be hydrolised during chlorination because as you said, the more halogen atoms are present, the faster this position will be further chlorinated and you will get chloroform even with excess of unreacted ketone (in alkaline medium)
i mean that, if you take a,a-dichloroketone(still it is correct name, because alpha means position "2", not "1") made beforehand, and treat it with alkaline you will get a-oxocarbonyl compound "For example, the alkaline hydrolysis conditions generated methylglyoxal. "

AndersHoveland - 4-5-2011 at 01:00

Even if the hydrolysis of the C--Cl bond was rapid enough, there would not be any significant quantities of methylglyoxal obtainable from the haloform reaction, as methylglyoxal is also an aldehyde (in addition to a ketone), and will therefore be oxidized in the hypochlorite solution very rapidly, faster than the chlorination of acetone.

I have been thinking... could something similar to the haloform reaction be done by bubbling NO2 into acetone?
Obviosly the solution could not be alkaline, since the nitrite that would form is not a reactive oxidizer, but the solution should not be too acidic either because a Meyer reaction on the nitroalkane would be undesirable.

[Edited on 4-5-2011 by AndersHoveland]

Ebao-lu - 4-5-2011 at 01:51

I have been thinking... could something similar to the haloform reaction be done by bubbling NO2 into acetone?

I think, it should be possible in the presence of Cu(2+) catalyst. There is a reaction of halogenation of acetone with CuX2 salt. I believe, the methanism is radical: one Cu2+ ion is coordinated with enolate or enol of acetone(with oxygen center), another Cu2+ is coordinated with X, then synchronously both copper atoms are reduced to Cu(I) with synchronous homolytic coupling of two radicals(not formed as free radicals, they form and couple synchronously)
I suppose same thing can happen with NO2 because it is a radical particle, and Cu2+ coordinated with enolate. NO2 can then oxidize Cu(I) to Cu( II), but this will result in formation of NO2- , that is a strong ligand and it may(not sure) occupy all copper 2+ and it will lose its catalytic activity, so oxidation of Cu(I) to Cu(II) should not be done with NO2. What can be used instead? Oxygen? Peroxide?

[Edited on 4-5-2011 by Ebao-lu]

AndersHoveland - 4-5-2011 at 02:21

Why not Ag(+) enolate reacting with NO2 ?

AgOC(CH3)=CH2 , NO2 --> Ag , O=C(CH3)CH2NO2

I do not know whether silver hydroxide, solubilized in an ammonia solution, and with some acetone mixed in, would work. Do you have a reference to that reaction in which acetone is halogenated using CuCl2 ? I believe the presence of halogen ions changes the reduction potentials by coordinating to the copper ion,
making Cu(+1) more favorable than otherwise. Indeed, iodide ions are known to reduce Cu(+2) ions to form a CuI precipitate and elemental iodine in solution.

[Edited on 4-5-2011 by AndersHoveland]

Ebao-lu - 4-5-2011 at 04:06

Yes, i've seen at least two refferences, one with chlorination with CuCl2, another with bromination. If you want, i can provide them (first i need to find them). Cl can make reaction different due to some reasons (like formation of stable CuX) so i am not sure about reation with NO2 yet, because there is no Cu(I) formation. On the other hand, it is possible to add some lithium chloride into solution, not sure that it can help though

It seems possible to use Ag, but price... you can recycle it, but still a 127g of silver can give only 1 mole of nitroacetone.. or 50ml approx. of nitromethane.. and it is not a catalyst
Better to make a catalytic cycle, or take a huge excess of copper/other metal salt.
Also, it is possible that this route would require absence of water(otherwise, NO2 can react with water to form HNO3 and HNO2, and HNO2 can nitrosate acetone into isonitrosoacetone), so a Cu2 based catalyst should be soluble in pure acetone (maybe some fatty acid salt?). Also even if initial reaction with nitroacetone formation is possible, after that many side reactions can occur, like further nitration of the same position of nitroacetone, or catalyst inactivation because obviously nitroacetone, rather then chloroacetone or acetone, would form enolate and coordinate with copper ion (because it may possess chelating properties)...

[Edited on 4-5-2011 by Ebao-lu]

[Edited on 4-5-2011 by Ebao-lu]

AndersHoveland - 4-5-2011 at 04:19

I was thinking rather that the nitroacetone would continue to be attacked, adding more nitro groups, until a
nitroformate (-)C(NO2)3 is able to ionize off.
Thus trinitromethane , not nitromethane should be the product. However, the (-)CH2NO2 intermediate is far more stable than the (-)CH2Cl, so I do not know if nitroacetone would easily hydrolyze to acetic acid and nitromethane before further attack by NO2. Whether this is so might not matter, as the aci-form of nitromethane CH2=NO2(-) is quite vulnerable to being oxidized, but this is usually only under alkaline conditions.

This seems surprising:
"Ethyl nitrolic acid (C2N2O3H4) was prepared by the action of potassium hydroxide and sodium nitrite on nitroethane" (Meyer & Constam, 1882).

As for possible nitrosation of the acetone,
nitrogen dioxide can oxidize organic nitroso compounds.
Nitrosobenzene is oxidized to nitrobenzene, whereas nitrosoalkanes are typically oxidized to pseudonitrosites (with a nitro and nitroso on the same carbon). Thus
CH3C(=O)C(=NOH)NO2 (acetylmethylnitrolic acid) may likely form.

I will save you the trouble of doing a search,
(the below has already been extensively discussed elsewhere in this forum)

"was prepared by mixing acetone with nitric acid (of 24% concentration) and a little fuming HNO3 and allowing the mixture to stand for 8 days at room temperature. An ether extraction gave on evaporation some acetylmethylnitrolic acid
Beil 3,621 and R. Behrend & H. Tryller, Ann283,221- 3( 1894)

"... right after the strong oxidation left behind was a clear, thick yellow oil of a pungent odor. According to Jahresbericht ├╝ber Fortschritte der Chemie (1902), Behrend and Tryller, p. 1075-77 this oil contained one-third to half acetylmethylnitrolic acid (CH3.CO.C(NOH).NO2) (cryst., mp. 62 deg., very decomposable) and other byproducts...

I do of course wonder if further nitrogen dioxide could react with acetylmethylnitrolic acid to form the intermediate CH3C(=O)C(NO2)3, since oximes are known to be oxidized by NO2 to pseudonitrosites. Such an intermediate would quickly hydrolyze to acetic acid and trinitromethane. But now I am getting off topic.

[Edited on 4-5-2011 by AndersHoveland]

Ebao-lu - 4-5-2011 at 12:39

Acetylmethylnitrolate is quite stable and thus not reactive, so i suppose addition of another NO2 with loss of conjugation will be too slow or not thermodinamically favorable, maybe even in case of radical nitration with NO2*, depending on the stability of acetylnitrolate or pseudonitrosite radicals. If acetylmethylnitrolic acid can be hydrolised into acetate and methylnitrolate, then methylnitrolic will be more vulnerable to any reaction, because its anion is not that stable. Maybe it will be possible to oxidize it with NO2 or something else to CH(NO3)3(several reactions of oxidation and nitrosation)

I don't know much about N-O compounds chemistry, so i can only write common things and proposals, and may be wrong

[Edited on 4-5-2011 by Ebao-lu]

AndersHoveland - 6-5-2011 at 14:46

There is a procedure for preparing Nitroform from Nitric Acid and Isopropanol in the topic "Trinitromethane" on this forum, suggesting that a "Haloform"-type reaction can also works with nitro groups instead halogen atoms.
(the moderator merged two of my posts together, while I was still editing the last one, messing up the post in several different ways, and this forum will not let me edit the problematic merged post)