Breaking Down Carbonyl Reaction Mechanisms: Anionic Nucleophiles (Part 1)

by James

in Aldehydes, Carboxylic acids, Drawing Reaction Mechanisms, Esters, Functional Groups, Ketones, Organic Chemistry 2

I’m going to spend today going into the mechanisms of some of the reactions in the summary sheet I posted last time. Like I said in that post, I think that about 98% of the mechanisms of the 110 combinations on the sheet can be adequately explained by five individual reactions: protonation/deprotonation, 1,2-addition, 1-2-elimination, 1-4 addition, and the SN2  [It goes to 100% if you include the E2].

I think it’s best to start a discussion of the mechanistic pathways of the reactions in this table by dividing the nucleophiles into two different classes : the anionic nucleophiles (Grignards, enolates, cyanide, alkoxides, hydroxide, and the hydrides) and the neutral nucleophiles (enamines, amines,  alcohols and water). While all of the reactions in the table still follow the essential rule of “nucleophile attacks electrophile“, there are some subtleties between these classes of nucleophiles as to the timing of the protonation steps. Furthermore, the reactions of some of the neutral nucleophiles can be facilitated by the use of acid catalysis, while acid would just destroy a number of the anionic nucleophiles (Grignards, for instance). So I’ll dedicate this first post to talking about the mechanisms of the anionic nucleophiles.

Note: while mechanisms are important, I think it’s easy to get too wrapped up in them. I’d say learn the principles first. Pound for pound,  knowing the trends and principles that govern the underlying chemistry will get you through an exam better than an intricate knowledge of mechanism. This is because multiple choice and short-answer exams are the preferred method of evaluation for most instructors: they allow for efficient evaluation of your understanding of chemical concepts, while not taking too much time to grade. I should write a post some time about the logistics of grading: let’s just say that the time and labor required to grade questions involving long written answers (e.g. mechanisms) can be extensive, especially for classes of >100 students. I am not saying don’t learn the mechanisms. I’m saying: make sure you have the basics (i.e. pKas, relative reactivities of carbonyl groups) down first, before you get bogged down in worrying about the details of, say, some intermediate proton-transfer step in the mechanism of the Aldol reaction.

OK. With that out of the way, for the reactions of anionic nucleophiles, there are really only 5 different patterns.

 Case 1: 1,2-addition followed by protonation (quench).

Case 2: 1,2-addition followed by 1,2-elimination. 

Case 3: 1,4-addition followed by protonation [check out row E]

Case 4:  SN2. (yep, that’s it)

Case 5: For lack of a better phrase, reaction failure. There are three main causes of this: 1) irreversible protonation of the nucleophile by the electrophile (e.g. Grignards with carboxylic acids) 2) trying to displace a strong base with a weak base [e.g. F7, failure of cyanide ion to displace OR from an ester) or 3) competing electrophilic sites (e.g. reactions of enones, where both [1,2] and [1,4] addition is possible).

Step Zero: Formation of the conjugate base (if it hasn’t been done already). Most of the anionic nucleophiles are “provided” in their anionic form, but enolates are a prominent exception. If you’re writing the mechanism of a base-promoted reaction like the Aldol or the Claisen, you’re usually given the neutral ketone or ester to start with. Ketones, esters, and other carbonyl compounds are poor nucleophiles by themselves, and slow to react with most electrophiles in any kind of meaningful way. However, once treated with a strong enough base, their reactivity pattern undergoes a drastic change: formation of their conjugate base (the enolate) makes them extremely strong nucleophiles. So make sure you know how to draw the conversion of a carbonyl compound into its enolate.

OK. So let’s look at the first two cases today (they are by far the most common) and finish up with the other three next time.

Case 1: [1,2]-addition / protonation

Relevant electrophiles: aldehydes, ketones.

Relevant nucleophiles: Grignards, enolates, cyanide, alkoxides, hydroxide, hydrides.

Important concepts to know:  1) Understand how steric factors affect the rate of addition of nucleophiles (i.e. they impede it). 2) Understand how electronic factors affect the electrophilicity of carbonyls (i.e. electron poor carbonyls are more reactive; learn the relative rankings of carbonyls, from electron-poor to electron rich).

Examples: Aldol reaction, cyanohydrin formation.
1-12addition

This is a very simple and familiar type of reaction. When a nucleophile attacks a carbonyl to give a tetrahedral compound, the reaction is called [1,2]-addition.  For the reactions of aldehydes and ketones with anionic nucleophiles, here’s the plot: Nucleophile attacks carbonyl to give a tetrahedral alkoxide. Alkoxide is protonated. The end.

All the additions of anionic nucleophiles to aldehydes and ketones on this table follow this outline. There is no subsequent [1,2]-elimination, as we will discuss shortly: the tetrahedral alkoxide, once formed, just sits around in solution until it is protonated (usually via water or mild acid quench). The [1,2]-elimination pathway to regenerate the carbonyl does not occur since that would involve expulsion of the extremely strong bases (i.e. bad leaving groups) hydride (pKa ~35) or alkyl (pKa ~50).


Case 2: [1,2]-addition followed by [1,2]-elimination. 

Relevant electrophiles: acid chlorides, anhydrides, esters

Relevant nucleophiles: Grignards, enolates, alkoxides, hydroxide, hydrides.

Relevant concepts: Everything for the [1,2]-addition (above) PLUS a knowledge of relative leaving group abilities (consult a pKa table).

Examples: Claisen condensation, saponification, transesterification.
2-12addition

These reactions begin by going through the [1,2]-addition as mentioned above to form a tetrahedral alkoxide. However, if there is another group present on the carbon that can serve as a halfway decent leaving group, this can be displaced by the anionic oxygen in the process of re-forming the carbon-oxygen double bond (π bond). This has the effect of switching out functional groups at the carbonyl: for example, the reaction of acid chlorides with alkoxides to provide esters. This is called [1,2]-elimination. 

There is a very strict rule governing this process. Just as the tetrahedral intermediate in the [1,2]-addition does not break down to liberate free H- or R- anions, weaker bases will not displace stronger bases from a carbonyl. So a knowledge of pKa values is essential in order to predict their outcome.  For example, here’s some relevant pKa values (pKa of conjugate acid in parentheses): R2N- (~35), RO (~17); AcO (~4); Cl (-7). Alkoxide (RO ) can displace AcO and Cl, but not R2N. Just remember that a weak base cannot displace a stronger base, just  as (in the absence of bribes that approximate Italy’s GDP) my 7-year old cousin’s Tim Bits junior girls soccer team will never, ever defeat AC Milan in a soccer match.

3-12addition-3

Sometimes the new carbonyl species generated is still reactive under the conditions and will undergo further reaction, assuming there is additional nucleophiles present. One example is in the Grignard reaction on acid halides. Addition of Grignard to an acid halide gives a ketone. The ketone, then, gets funnelled into the 1,2-addition/protonation manifold.

I’ll deal with the remaining 3 cases in Part II.

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Sarah

You are my hero. I think I might actually get an A on my orgo exam next week. I love you

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