Examkrackers Chemistry - Imine/Enamine formation

[howtomedicine]

I'm currently reading the Examkrackers 2015 Chemistry book(page. 100) and the mechanism for imine/enamine formation begins with the amine attacking the carbonyl carbon of the aldehyde/ketone as the first step. When i've looked up the mechanism on other sites, the first step of imine/enamine formation is protonation of the carbonyl oxygen THEN the amine attacking.

I'm not sure which mechanism is correct because the MCAT THINK question right below the mechanism states: What would happen if an acid catalyst were added at the beginning of the reaction instead of after the first reaction(amine attacking the carbonyl oxygen) had occurred? The explanation they provided was that the amine would be protonated and will no longer act as a nucleophile.

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[theonlytycrane]

An acid catalyst is needed for the reaction otherwise the reaction will be really slow. An acid catalyst helps -OH leave as H2O. Will some amine get protonated? Yes. But in a lab you can think about adjusting concentrations of reagents (use excess nucleophile) to push the reaction forward.

 

[aldol16]

The explanation given in your book is not entirely accurate. Think back to carbonyl chemistry. What are some ways to activate the carbonyl? Adding an acid is one way. Acids tend to make the carbonyl more electrophilic. Imagine protonating the carbonyl oxygen. That adds a positive charge on the carbonyl oxygen, making it draw even more electron density towards it. This is commonly used in synthesis to activate a carbonyl to nucleophilic attack. Now, the reason why your book is not entirely right is because you could also have a Lewis acid that does the same thing. A Lewis acid catalyst would not protonate anything. Imagine just adding Ca2+ or Mg2+ to the system (as is common in biological systems). The Lewis acid will accept a lone pair from the carbonyl oxygen, again giving it more positive character and thus activating the electrophilic character of the carbonyl. In that case, the reaction would accelerate since before, you had a weak nucleophile attacking a moderate electrophile. After the Lewis acid is added, you have a weak nucleophile attacking a strong electrophile - much more energetically favorable.

Now, back to the protonation scenario (say you added a Bronsted acid). Well, whether that accelerates the reaction or slows it down depends on whether the carbonyl oxygen or the amine wants the proton more - in other words, their pKa.

 

[howtomedicine]

Thank you for the replies, makes a lot more sense now

 

[NextStepTutor_2]

I'm currently reading the Examkrackers 2015 Chemistry book(page. 100) and the mechanism for imine/enamine formation begins with the amine attacking the carbonyl carbon of the aldehyde/ketone as the first step. When i've looked up the mechanism on other sites, the first step of imine/enamine formation is protonation of the carbonyl oxygen THEN the amine attacking.

I'm not sure which mechanism is correct because the MCAT THINK question right below the mechanism states: What would happen if an acid catalyst were added at the beginning of the reaction instead of after the first reaction(amine attacking the carbonyl oxygen) had occurred? The explanation they provided was that the amine would be protonated and will no longer act as a nucleophile.

The concept of "priming" a carbonyl for attack with an acid has traditionally been an MCAT favorite when it comes to orgo questions. As stated above, it's all about understanding the role induction of e- density plays in nucleophile attack. This is further illustrated in the key differences between Sn1, Sn2 and (formerly on the MCAT) E1/E2 reactions. pH also a key regulator of reversible/irreversible esterification and other biologically relevant reactions (Claissen condensation, oxidation, etc...)

Hope this helps, good luck!