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Author Topic: Can my thoughts regarding this mechanism be confirmed/corrected?  (Read 957 times)

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masspecs

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In the picture, Ethyl 2-oxocyclopentanecarboxylate (I) reacts with ethyl 2-(4-chloromethylphenyl)propionate (II) in the presence of KOH in hot DMF to afford ethyl 2-[4-(1-ethoxycarbonyl-2-oxocyclopentan-1-ylmethyl)phenyl]propionate (III), which is then hydrolyzed and decarboxylated by treatment with 47% HBr in refluxing dioxane. I'd just like to walk my way through this and see if my theories regarding the mechanism are correct.

 - (I) has an α carbon that is deprotonated (the one beside the ester group). This creates a carbanion that is stabilized both by resonance as an enolate and inductively by electron withdrawing from the ester group. This stability leads to marginal nucleophilicity; chlorine is a marginal leaving group here (although the carbocation is resonance stabilized by the aromatic ring), and no inversion is observed, which leads me to believe an SN1 rxn occurs between (I) and (II) to yield (III). DMF is used as a solvent so as not to inhibit nucleophilicity by using a polar protic solvent.
 - It's not specified, but I suspect (III) can be  captured via distillation to due boiling point/density differences between it and (I) and (II).
 - (III) is reacted with HBr in dioxane (I'm not sure why 47% is used; I'm assuming at STP, it's the maximum concentration of HBr(g) in water) is used, as dioxane is relatively stable at extremely high and extremely low pH values. The hydronium acts as an impetus for hydrolysis on the ester groups on both rings. I think the Bromide anion acts as just a counterion here (but I'm not sure why).
 - The step where (III) is reacted with sodium hydroxide is where I get lost. I'm not sure how the sodium hydroxide spurs decarboxylation and selective decarboxylation, at that (why not the ester on the aromatic ring as well?).



« Last Edit: June 14, 2018, 07:33:19 AM by masspecs »
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wildfyr

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #1 on: June 14, 2018, 09:21:49 AM »

1. The benzyl chloride isn't a stereocenter, How do you know no inversion is observed?
Typically on the prep scale, column chromatography would likely be used here. II isn't going to be very volatile.

2. I agree with your analysis of the HBr use.

3. The NaOH deprotonates the carboxylic acid, but its really the heat doing the work once that happens. What do you think is the driving force for the decarboxylation? Hint: think thermodynamics. I'm assuming this step is also done at reflux?

On the topic of selectivity, what is the degree of substitution at those two carbon centers, and why might one be a better spot for decarboxylation than the other?

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masspecs

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #2 on: June 14, 2018, 10:00:11 AM »

1) I assumed no inversion occurred because the given image is all that was given (and the introductory paragraph) regarding the mechanism. I guess that (II) is electrophilic, so it's attacked by the carbanion on (I), but what type of substitution reaction would that be?

2) There's a β-ketoacid on the moiety from (I), so keto-enol tautomerism will occur leading to decarboxylation? But if that happens, why is the NaOH necessary?

3) I'm guessing the selectivity comes from resonance stabilization due to the phenyl ring? It doesn't need the decarboxylation to occur (or it's just a minor product).
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wildfyr

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #3 on: June 14, 2018, 05:34:40 PM »

If stereocenter cannot occur at that point, then you can't use that as a factor in determining the mechanism. These structures say nothing with regards to whether inversion occurs or not. Someone should correct me if they know directly, but my gut says SN2, I believe its more favor than SN1 at a benzylic position

2. Keto-enol tautomerization is just part of a word pasta you are trying to throw against the wall. How could it lead to decarboxylation?

You have a highly acidic ester hydrolysis reaction mixture that gives a carboxylic acid, what do you think NaOH does? What form does the carbonyl functional group need to be in to decarboxylate? The answer is literally in the name. Why  would this substance want to go from a single liquid molecule to a 2 new molecules, 1 of them a gas. Once again, my hint is in thermodynamics. Look at the Gibbs free energy equation.

3. I'm not even looking at the phenyl, just simple degree of substitution. Which forms a more stable carbocation once CO2 is released?
« Last Edit: June 15, 2018, 02:49:57 AM by wildfyr »
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hypervalent_iodine

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #4 on: June 14, 2018, 07:21:41 PM »

If stereocenter cannot occur at that point, then you can't use that as a factor in determining the mechanism. These structures say nothing with regards to whether inversion occurs or not. Someone should correct me if they know directly, but my gut says SN2, I believe its more favor than SN1 at a benzylic position

2. Keto-enol tautermization is just part of a word pasta you are trying to throw against the wall. How could it lead to decarboxylation?

You have a highly acidic ester hydrolysis reaction mixture that gives a carboxylic acid, what do you think NaOH does? What form does the carbonyl functional group need to be in to decarboxylate? The answer is literally in the name. Why this substance want to go from a single liquid molecule to a 2 new molecules, 1 of them a gas.

3. I'm not even looking at the phenyl, just simple degree of substitution. Which forms a more stable carbocation once CO2 is released?

I was under the impression that SN1 was often favoured at benzylic positions due to added resonance stabilisation of the carbocation.
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clarkstill

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #5 on: June 14, 2018, 08:52:44 PM »

If stereocenter cannot occur at that point, then you can't use that as a factor in determining the mechanism. These structures say nothing with regards to whether inversion occurs or not. Someone should correct me if they know directly, but my gut says SN2, I believe its more favor than SN1 at a benzylic position

2. Keto-enol tautermization is just part of a word pasta you are trying to throw against the wall. How could it lead to decarboxylation?

You have a highly acidic ester hydrolysis reaction mixture that gives a carboxylic acid, what do you think NaOH does? What form does the carbonyl functional group need to be in to decarboxylate? The answer is literally in the name. Why this substance want to go from a single liquid molecule to a 2 new molecules, 1 of them a gas.

3. I'm not even looking at the phenyl, just simple degree of substitution. Which forms a more stable carbocation once CO2 is released?

I was under the impression that SN1 was often favoured at benzylic positions due to added resonance stabilisation of the carbocation.

Both SN1 and SN2 reactions are accelerated at benzylic positions - conjugation lowers the energy of the SN2 transition state (and raises the energy of the starting material by weakening the C-Cl bond).

So whether it's an SN1 or SN2 can't be gleaned just from the choice of electrophile. However, the use of a polar aprotic solvent is more consistent with SN2, as is the use of a charged and relatively nucleophilic nucleophile.
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masspecs

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #6 on: June 20, 2018, 05:38:22 AM »

I initially thought SN2; the given reaction scheme didn't say anything about inversion. However, I now realize there's no chiral center at the C-Cl-H-H center.
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kriggy

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Re: Can my thoughts regarding this mechanism be confirmed/corrected?
« Reply #7 on: June 20, 2018, 08:31:49 PM »

But the chiral center is on the keto ester. Assuming it was enantiomericaly pure, the alpha deprotonation and enolate formation will lead to racemic product III due to the planarity of the enolate.
THe fact that it is SN1/2 doesnt matter because the chiral molecule is nucleophile not electrophile.
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