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With which group does the middle oxygen atom of an anhydride remain, on hydrolysis? As an example, let us say we have the following modification of ethanoic methanoic anhydride, with the middle oxygen atom being the $\ce{^18O}$ isotope:

modified ethanoic methanoic anhydride

On acid catalysed hydrolysis with normal water, is this isotope found in formic acid, or acetic acid, or in both (i.e., hydrolysis is random and hence the product contains both the acids with both types of oxygen atoms)?

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    $\begingroup$ I think it will be largely random, maybe with slight prevalence of one side. $\endgroup$ – Ivan Neretin Apr 27 '18 at 5:22
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    $\begingroup$ This is an interesting question. Moreover, what if the given example was of some beta branched anhydride? Would then, due to steric repulsions, the $\ce{O^{18}}$ be dominantly present in one of the acid product? It would be even more interesting to see if some research has taken place on this topic. $\endgroup$ – Gaurang Tandon May 1 '18 at 4:23
  • $\begingroup$ @GaurangTandon The first step, i.e. the protonation of the middle oxygen is obviously clear, and I don't believe $H^+$ suffers any steric repulsion (I may be wrong, but I have never seen any example of that). Then the answer would probably be something like "the better leaving group leaves". But then I have never seen this mentioned in any book so it might well be dependent on the conditions. $\endgroup$ – dryairship May 1 '18 at 5:17
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    $\begingroup$ I'm not sure this is a meaningful question. Is there isotopic scrambling as a result of being in an acidic aqueous medium?? $\endgroup$ – Zhe May 4 '18 at 12:56
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What I think is, the marked oxygen atom will stay with acetic acid because the carbon on the right side of the oxygen isotope has a slightly more δ+ charge than the carbon on the left due to the +I effect of methyl group attached to it. So, the marked oxygen should go with acetic acid instead of formic acid in the major product.

For the reaction the mechanism is usually tetrahedral. Only under acid catalysis does the SN1 mechanism occur and seldom even then.

The tetrahedral reaction mechanism of hydrolysis of anhydrides is similar to that for the hydrolysis of carboxylic esters which usually also proceeds through the tetrahedral mechanism.

Of the eight mechanisms given by Ingold for ester hydrolysis, seven have actually been observed in hydrolysis of carboxylic esters. The one that has not been observed is the BAC1 mechanism. The most common mechanisms are the BAC2 for basic catalysis and the AAC2 for acid catalysis, that is, the two tetrahedral mechanisms. Both involve acyl-oxygen cleavage.

So considering the mechanisms for ester hydrolysis and anhydride hydrolysis to be similar, it can be proved that the extent of δ+ charge on the carbon being attacked does play a major role in deciding the rate of reaction.

For instance, the rate of hydrolysis for the following esters is in the order shown:

enter image description here

So I think this should be enough to prove what I stated in the very beginning of my answer.


Source: Jerry March Organic Chemistry 6th edition, Organic chemistry by Paula Yurkanis Bruice.

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  • $\begingroup$ Two users (Zhe and user55119) have already said the isotopic oxygen will be present in both the acids as a product. I appreciate your responses, but I would really recommend you back up your idea with some evidences/papers. Thank you. $\endgroup$ – Gaurang Tandon May 7 '18 at 1:01
  • $\begingroup$ @GaurangTandon that's the reason I especially mentioned "in the major pdt" in the last line of my answer. $\endgroup$ – Carrick May 7 '18 at 6:35
  • $\begingroup$ Thanks for the additional details. The new addition seems to speak about the rate of hydrolysis, rather than the migration of any isotopic atom towards any group. So I fail to see the connection here, and I am not sure how they both relate to each other. Can you please tell how? $\endgroup$ – Gaurang Tandon May 7 '18 at 12:57
  • $\begingroup$ @GaurangTandon I talked about rate of hydrolysis to show that the attack will be more frequent on the carbon to the right of the isotopic oxygen rather than the left one and so the isotopic oxygen will majorly be with the acetic acid molecule. $\endgroup$ – Carrick May 7 '18 at 13:24
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The mixed anhydride, acetic formic anhydride (AFA), was first prepared by Béhal in 1899 who formed it by dissolving formic acid in acetic anhydride (AFM) in 1:1 mole ratio (Béhal, Compt. rend., 1899, 128, 1460)[1]. It was described as a liquid with an odor similar to that of acetic anhydride, boiling at about $\pu{29 ^\circ C}$ at a pressure of $\pu{18 torr}$. Similar to formic anhydride, which decomposes to formic acid and carbon monoxide ($\ce{CO}$) at room temperature within hours, AFA also decomposes slowly to acetic acid and $\ce{CO}$ by long standing at room temperature. For example, $\pu{50 mL}$ of AFM in a 100 mL volumetric flask with a rubber stopper had suddenly exploded after standing undisturbed for about 2 weeks [2]. Only $\ce{CO}$ (by flame test) and acetic acid in the flask were detected. The reaction was described as: $\ce{HC(=O)OC(=O)CH3 -> CO + CH3COOH}$.

The decomposition of AFA is accelerated by increasing temperature and types of catalyst used, and also depends upon the solvent used[1]: for instance, it is very fast in aprotic solvents such as toluene, carbon tetrachloride, and nitrobenzene, but slow in protic solvents such as ethanol, I-pentanol, and 2-methylpropanol (note that AFA undergoes formylation reaction of alcohols, instead of decomposition to $\ce{CO}$ and acetic acid; [3]). The catalyst for the decomposition could be either an acid (e.g., $\ce{H2SO4}$, $\ce{HNO3}$, $\ce{HF}$, $\ce{HCl}$, etc.) or tertiary amine bases (e.g., N,N-dimethylbenzeneamine, brucine, strychnine, nicotine, etc.), either of which produces $\ce{CO}$ and acetic acid. Note also that, a mixture of anhydrous $\ce{HF}$ and AFA at $\pu{0 ^\circ C}$ and atmospheric pressure produced formyl fluoride ($61\%$) with small amount of acetyl fluoride [4]. It’s noteworthy to mention that formyl fluoride is the only known stable halide of formic acid. The above reaction, however, depends on even relatively minor variations of conditions. For example, the reaction performed at room temperature instead of $\pu{0 ^\circ C}$ has yielded almost equimolar amounts of the formyl and acetyl fluorides [4]. Based on all of these evidences, it is safe to suggest that the most susceptible carbon center of AFA to a nucleophilic attack is the carbonyl carbon of its formyl group, but very sensitive to the reaction conditions.

Olah and others have done excellent work on AFA protonation [5]. According to $\ce{^1H}$ NMR evidence, they suggested rapid proton exchange between carbonyl oxygen atoms (observable at $\pu{-85 ^\circ C}$) of AFA and its eventual decomposition by excess super acids to protonated acetic and formic acids, acetyl cation, and formyl cation intermediate, which is not detected even at $\pu{-130 ^\circ C}$, but rapidly decomposed to $\ce{CO}$. Suggested mechanism and $\ce{^1H}$ NMR evidence are as follows:

AFA Mechanism

Since, AFA gives formylated alcohols under similar condition in alcohols, the following mechanism can be suggested:

Hydrolysis of AFA

Yet, the major and minor product ratio is extremely depends on reaction conditions due to high sensitivity of AFA to its atmosphere.

Following example shows it can be used to selectively acylate (formylate) vide variety of heteroatoms if conditions are used accordingly [6].

N-Formylbenzotriazole


References:

  1. Strazzolini, P.; G. Giumanini, A.; Cauci, S. Acetic formic anhydride a review. Tetrahedron 1990, 46 (4), 1081-1118. DOI: 10.1016/S0040-4020(01)86676-X.

  2. Schierz, E. R. The Catalytic Decomposition of Formic Acid in Acetic Anhudride: J. Am. Chem. Soc., 1923, 45(2), 455-468. DOI: 10.1021/ja01655a022.

  3. Stevens, W.; van Es, A. Mixed Carboxylic Acid Anhydrides: II. Esterification of alcohols with the formic acid/acetic anhydride reaction mixture: Rec. Trav. Chim., 1964, 83(12), 1287-1293. DOI: 10.1002/recl.19640831212.

  4. Olah, G. A.; Kuhn, S. J. Formylation with Formyl Fluoride: A New Aldehyde Synthesis and Formylation Method1. J. Am. Chem. Soc. 1960, 82 (9), 2380-2382. DOI: 10.1021/ja01494a065.

  5. Olah, G. A.; Dunne, K.; Mo, Y. K.; Szilagyi, P. Stable carbocations. CXXVIII. Protonated acyclic carboxylic acid anhydrides and their cleavage to oxocarbenium ions. Question of the formyl cation in superacid media. J. Am. Chem. Soc. 1972, 94 (12), 4200-4205. DOI: 10.1021/ja00767a027.

  6. Practical and Efficient Synthesis of N-Formylbenzotriazole: Org. Synth., 2013, 90, 358-366. DOI: 10.15227/orgsyn.090.0358.

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    $\begingroup$ As always, a very comprehensive answer! :D Just one thing, I don't understand how the first two paragraphs of your answer relate to the question being asked, as there is no mention of isotopic oxygen atoms in them. So, what purpose do they serve? $\endgroup$ – Gaurang Tandon May 9 '18 at 1:43
  • $\begingroup$ @Gaurang Tandon: We don't use isotope experiments in everyday lab. They are used to solve some problems in reaction mechanisms (e.g., deuterium isotope effect). In my paragraph, I generally talked about stability and reactivity of the compound without isotope label to give the expecting results to a reader. $\endgroup$ – Mathew Mahindaratne May 9 '18 at 15:53
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This mixed anhydride is used to make formate esters of alcohols. Productive protonation will occur on the formate carbonyl oxygen followed by nucleophilic addition of water and loss of labeled acetic acid (either oxygen site; resonance) and unlabeled formic acid as the kinetically formed products. The $\ce{O^{18}}$ label in acetic acid will eventually exchange with water to form $\ce{O^{18}}$ water in an equilibrium mixture. Ultimately, the $\ce{O^{18}}$ label will also work its way into formic acid by acid-catalyzed exchange with $\ce{O^{18}}$ water.

References: For the reactivity of acetic formic anhydride with nucleophiles, click here.
For the kinetics of O18 exchange between carboxylic acids and water, click here. [R. L. Redington, J. Phys. Chem., 1976, 80, 229.]

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  • $\begingroup$ Sorry, but what is "productive protonation"? $\endgroup$ – Gaurang Tandon May 5 '18 at 6:19
  • $\begingroup$ There are three oxygens that can be protonated reversibly. Only protonation of the formyl oxygen leads to further reactions. $\endgroup$ – user55119 May 6 '18 at 1:35
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    $\begingroup$ Really, the oxygens on carboxylic acids exchange with water?! Do you have a reference for that? I've never heard of that before; I'd like to read more. $\endgroup$ – hBy2Py May 7 '18 at 2:18
  • $\begingroup$ @hBy2Py I assumed this is what Zhe meant by "isotopic scrambling" in his comment to the question, but now I'm not sure if that's actually what user55119 actually meant as well :/ $\endgroup$ – Gaurang Tandon May 7 '18 at 6:37
  • $\begingroup$ @hBy2Py; Checkout the mechanism of Fischer esterification. If O-18 alcohol can incorporate and form labeled ester, why not O-18 water to form labeled carboxylic acid? $\endgroup$ – user55119 May 7 '18 at 15:53
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The oxygen would remain more often with the aceto group, but I'm sure you would get a mixture of products. The aldehyde moiety is more electronegative than the ketone moiety of the anhydride so would be preferentially attacked by the water molecule during hydrolysis. Also, the aldehyde portion would be more sterically accessible to the attack.

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