Enolates have a lot in common with alkenes. They are flat and have a C-C pi bond.
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If you aren’t familiar with enolates and need more background, go back and read the previous post on enolates first. [See post: Enolates]
Many ketones are capable of forming two different enolates, depending on which alpha-carbon is deprotonated.
The question is, which one will be favored?
Generally enolates are flat and can be thought of as similar to alkenes, even if they tend to react with electrophiles like they are carbanions.
Going back to Zaitsev’s rule, we’ve seen many examples where alkenes increase in stability as the number of H atoms directly attached to the ring decreases. ( or conversely, as the number of attached carbons increases )
In other words, the more substituted the alkene, the more stable it is. [ Note 1 ]
This also applies to enolates. The fewer C-H bonds there are on the alkene, the more thermodynamically stable it is.
Ketones can undergo deprotonation with strong bases like alkoxides RO(-) to give enolates.
Alkoxides are not as basic as ketone enolates, so the acid-base equilibrium tends to favor the starting ketone. However, they are still strong enough bases to set up an equilibrium between the starting ketone and the two different enolates.
The position of that equilibrium will favor the most thermodynamically stable enolate (i.e. the most substituted), even though it is slightly slower to form due to the fact that the C-H bond is more sterically hindered.
For that reason we call the more substituted enolate the thermodynamic enolate because of its greater stability.
We also say that formation of this enolate is under thermodynamic control.
The equilibrium ratio of enolates will depend on the difference in energy between their heats of formation (which is typically 1-2 kcal/mol). As a rough rule of thumb, 4:1 is a good ballpark number but it can vary considerably. [ Note 2 ]
These “thermodynamic” enolates can act as nucleophiles in various reactions.
Any time we form an enolate under thermodynamic control, we should expect that the major product will arise from the reaction of the more substituted enolate with the electrophile, such as in this halogenation reaction. [ Note 3 ]
Similarly, this will also be the case in these examples of the Aldol reaction, enolate alkylation, and conjugate addition. [ Note 4 ]
You may ask, “is that it?”
Are we doomed by this thermodynamic preference of the enolate to never be able to form the other less substituted enolate, just because it screams out, “Thermodynamically, I don’t wanna!“.
No! There’s a workaround!
There are lots of times we might want the less-substituted enolate. So here is a strategy for how to go about making it.
The first thing to note is that the hydrogen on the more-substituted side is slightly more difficult to access due to the presence of the extra alkyl group.
That’s why there is a higher energy barrier for deprotonation in the energy diagram (above).
So what if we were to use a base that is extremely sterically hindered?
In that case the reaction with the more sterically hindered proton should be very slow, and reaction with the less sterically-hindered protons on the other side should be fast.
A good choice for this is the strong bulky base, lithium di-isopropyl amide (LDA).
LDA has two big and bulky isopropyl groups flanking a very basic amide base. The pKa of the conjugate acid is 38, so deprotonating a ketone alpha-carbon (pKa 16-18) is no problem for LDA.
Also, unlike alkoxide bases RO(-), deprotonation goes to completion. So long as an excess of base is used, there is no equilibrium between the different enolates. [ Note 5 ]
LDA is so strong that deprotonation can happen at extremely low temperature. This helps us because we can use low temperatures to slow down that undesirable acid-base reaction even more.
So when our ketone is treated with LDA at low temperature we get preferential formation of the less-substituted enolate. We call this, “kinetic control”.
Note that there is nothing magic about -78°C. That just happens to be the temperature of the convenient (and cheap) dry ice-acetone cooling bath.
We call the less substituted enolate the “kinetic enolate” because we are depending on the difference in reaction rates (“chemical kinetics” remember?) to give us selectivity.
Note that enamines can also be used for performing reactions at the less-substituted alpha carbon . [ Note 6 ]
Kinetic enolates can be used for the same reactions of enolates we’ve seen previously, such as alkylation, the Aldol reaction, and halogenation.
In each case we are forming our new bond at the less substituted alpha carbon of the ketone.
There’s another advantage to using LDA. Since LDA is such a strong base, we can use it form some of the less-accessible enolates of carboxylic acid derivatives such as esters, amides, and nitriles.
These enolates can perform the same types of reactions as those we’ve seen above, such as alkylation and conjugate addition.
In short, LDA is an extremely useful strong base that can form just about any enolate you need, provided that the C-H bond isn’t sterically hindered. [ Note 7 ]
So what have we learned?
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Note 1. A rough rule of thumb is that each C-H you replace with a C-C gets you an additional 1 kcal/mol of stability. This might not sound like a lot, but even 1 kcal/mol is enough to give you about 80:20 equilibrium ratio.
Note 2. “it can vary considerably”. A typical ratio of thermodynamic:kinetic enolates under “thermodynamic conditions” (NaOR/ROH) is about 4:1 but it can be significantly larger than that. The identity of the alkali metal counter-ion can have a huge role. Page 2 of this article provides a great overview on forming thermodynamic enolates.
Note 3. .This reaction can be hard to control! One problem with halogenation of ketones under thermodynamic conditions (RO(-) / ROH) is that the halogenation product is more acidic than the starting ketone. This can easily lead to multiple halogenations, as in the Haloform reaction.
Note 4. For more on alkylation of ketones under thermodynamic conditions, see this classic study. It turns out the reaction of the ketone with NaOR/CH3I does indeed put CH3 on the more substituted enolate (in 41% yield), but there are lots of byproducts due to over-alkylation. For the purposes of our course, this is why procedures like the acetoacetic ester synthesis are preferred for enolate alkylation.
Note 5. “No equilibration between the enolates” . If less than 1 equivalent of strong base is used, it’s possible to end up with the thermodynamic enolate after some time has elapsed.