Concept: General Reaction2m
Hey guys! Now we’re going to talk about one of the more important mechanisms in this course. That is mechanism of Fischer Esterification. Fischer Esterification is just another name for acid-catalyzed esterification. When we think about what that is, that would just mean that I’m taking a carboxylic acid and reacting it with alcohol in the presence of acid and I’m getting an ester. I'm getting an ester product hence the term esterification. According to our three rules, this is a totally fine reaction because we said that carboxylic acid and esters have about the same reactivity. It’s pretty easy to switch between the two. According to my three rules, I know this is a favored reaction that this can work. Then why do I have this video? Because it turns out that professors just love to ask about this mechanism because it’s one of the fundamental mechanisms of nucleophilic acyl substitution. That’s why I’m going to go into depth and we're going to draw the whole mechanism for this from scratch. Let's go ahead and do that now.
Concept: General Mechanism5m
So, if you've been following clutch for a while or if you're just naturally good at Orgo it shouldn't be so hard because we're going to see these recurring themes of these acid catalyzed reactions that just keep happening over and over with just minor adjustments, okay? So, one thing before begin, I hope you guys are okay with me using a protonated version of alcohol as my acid because I don't want to have two different things hanging around. So, I'm just going to let you guys know that alcohol plus H plus, my acid, is going to give me ROH2 plus, which is what I'm going to use my acid, okay? So, if you couldn't see that I'll move it up a little bit. Okay cool. So, I'm going to say H-ORH positive, my first step is going to be, you got it, protonation, because it's acid catalyzed. So, it's going to give me something looks like this OH, OH positive, we know this is going to open up the opportunity for a resonance structure. So, let's draw that, okay? Again guys, if you look in your textbook or if you watch your professor drawing this, they may not include this resonance structure but it's okay, because it's still valid, all the arrows are going in to the same place, I'm just splitting it up a little bit better, okay? So, Now this is a perfect environment for a nucleophilic addition, right? So, I'm going to take my alcohol, I'm sorry, a nucleophilic attack, I'm going to take my alcohol and I'm going to make this intermediate, what do we have? we have OH, OH, OHR and then our R group and this has a positive, okay? So, at this point look, what we've done so far, we've done protonation, we have done a nucleophilic attack and now what are we going to do? Well, guys, we're trying to get rid of one of the OH's to replace it with OR. So, we're going to do a proton transfer so we can get rid of one of those ovations so this is going to be proton transfer, after I do that I get a molecule, looks like this, where now I have OH2 positive, OR and my R group.
Now, guys I can do an elimination reaction where the lone pair from my O comes down and kicks out my water, what that gives me is now a compound looks like this, and what's my last step? my last step is deprotonation with the original alcohol to regenerate my catalytic acid. So, at the end I'm going to get an ester and guess what guys, this is a completely reversible reaction. So, if we wanted to take every step backwards we could. Alright, make sense? Guys, so I'm not sure if you guys have seen these mechanisms already or not but if you look at the mechanisms of acetals or if you look at the mechanisms of amines, these our carbonyl reactions that are, I have videos for in other parts of your clutch textbook, right? And, if you look at those mechanisms you're going to see so many similarities, these mechanisms just keep kind of like replicating themselves, okay? By the way, I forgot to say this was elimination and this was deprotonation. Awesome guys, are you getting a little better at mechanisms? hopefully, I hope so, I hope I'm making a little easier for you, let's move on to the next reaction.
Draw the structure of the major organic product(s) of the reaction.
What product would you expect to obtain from the following reaction?
Suggest the most appropriate reagent for each synthesis, and explain your choice.
Complete the mechanism for this acid-catalyzed transesterification by drawing out all the individual steps. Draw the important resonance contributors for each resonance-stabilized intermediate.
(a) Show how you would use acetic anhydride and an appropriate alcohol or amine to synthesize (i) benzyl acetate, (ii) N,N-diethylacetamide.
(b) Propose a mechanism for each synthesis in part (a).
The mechanism of the Fischer esterification was controversial until 1938, when Irving Roberts
and Harold Urey of Columbia University used isotopic labeling to follow the alcohol oxygen
atom through the reaction. A catalytic amount of sulfuric acid was added to a mixture of 1 mole
of acetic acid and 1 mole of special methanol containing the heavy isotope of oxygen.
After a short period, the acid was neutralized to stop the reaction, and the components of the
mixture were separated.
(a) Propose a mechanism for this reaction.
(b) Follow the labeled 18O atom through your mechanism, and show where it will be found
in the products.
(c) The 18O isotope is not radioactive. Suggest how you could experimentally determine the
amounts of 18O in the separated components of the mixture.
Show how Fischer esterification might be used to form the following esters. In each case, suggest a method for driving the reaction to completion.
(a) methyl salicylate
(b) methyl formate (bp 32 °C)
(c) ethyl phenylacetate
Most of the Fischer esterification mechanism is identical with the mechanism of acetal formation. The difference is in the final step, where a carbocation loses a proton to give the ester. Write mechanisms for the following reactions, with the comparable steps directly above and below each other. Explain why the final step of the esterification (proton loss) cannot occur in acetal formation, and show what happens instead.
Predict the product. NOTE: the product has 6 oxygens
What is the best choice of reagent(s) to perform the following transformation?
a CH3OH, H2SO4
b CH3I, H2SO4
Draw the organic product(s) for the following reaction. Indicate stereochemistry where appropriate. Assume an aqueous workup, when necessary. A reasonable answer may be “ No Reaction.”
Draw a reasonable mechanism for the reaction below.
Provide a detailed mechanism for the esterification reaction below.
Which of the following is (are) tetrahedral intermediate(s) in the acid catalyzed esterification of benzoic acid with ethanol?
In the acid catalyzed esterification of compound 1, several possible intermediates are shown. Indicate the order in which these intermediates would appear during the conversion of 1 into 2.
a) 1 → I → IV → V→ III → 2
b) 1 → II → IV → 2
c) 1 → III → IV → I→ V → 2
d) 1 → III → I → V→ IV → 2
e) 1 → I → III → IV → 2
Provide a detailed reaction mechanism for the following transformation. This is an intramolecular version of what type of reaction?
Fischer Esterification is an acid-catalyzed method to turn carboxylic acids into esters through nucleophilic acyl substitution.
Fischer esterification (aka Fischer-Speier esterification and acid-catalyzed esterification) is a great way to take a carboxylic acid and convert it into an ester. All that’s required is a carboxylic acid, a strong acid catalyst, and an alcohol. Let’s go ahead and use acetic acid, H3O+ (same as writing H+), and ethanol to demonstrate the mechanism. To be clear, any acid like H2SO4 or HCl works just fine; we’re just going to use protonated water here.
The first step of this reaction is the protonation of the carbonyl oxygen to form an electrophilic carbon. Either resonance form can be used for the rest of the mechanism.
The alcohol then comes in and attacks the carbon to form a tetrahedral intermediate.
Next an intramolecular proton transfer occurs to form a hydronium ion.
Once that happens, the carbonyl is reformed and water is kicked off.
All that’s left to do is deprotonate the carbonyl.
Now that you've learned about Fischer esterification, you know the game plan for nucleophilic acyl substitution (NAS). NAS can be used to make tons of molecules like benzoic acid and aspirin!
Notice that we ended up with our acid again? That’s why this is considered an acid-catalyzed mechanism. Of course, there’s also base-catalyzed esterification. Be sure to check out my lesson dedicated to carboxylic acid derivatives. Good luck studying!
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