Concept: Concept: Unusual Acidity of the Alpha Carbon2m
In this video, I’m going to introduce two very important new concepts that we need to know for this section. That’s the concept of carbons and tautomerization.
Previously to this chapter, we've discussed how carbonyl carbons are very reactive because they have a partial positive on them. So far, we’ve always been talking about reactions at the carbonyl carbon. It turns out that carbonyls have another reactive component other than the carbonyl carbon. This is evidenced by pKas. I know it's been a long time since your acid and base chapter in Orgo 1. But does anyone happen to remember what is the pKa of an sp3-hybridized CH bond? Basically an alkane. Do you guys remember what the pKas of just a typical alkane? I heard someone say it. Great job. It's been forever since we’ve mentioned that. It’s 50. If you said 45, anything above. It’s 50. It’s something really high, something crazy high. The acidity of a normal alkane is 50. But alpha-carbons are uniquely acidic. Alpha-carbons don’t have a pKa of 50. Guess what their pKa is. 20. What is responsible for this crazy difference? Just so you guys know, this is on a log scale. That means that it’s 10 to the thirty times more acidic than an alkane. That’s an indescribable number. That's a huge, huge number. What could possibly be responsible for this difference? The answer is tautomerization. That's what I’m going to show you guys in the next video.
Concept: Concept: Tautomerization Mechanisms6m
So guys, tautomerization is a phenomenon that naturally happens to all ketones and aldehydes in an aqueous environment, okay? And there's base catalyzed versions and there's acid catalyzed versions, we're going to learn both, but essentially what happens with tautomerization is that whenever you tautomerize a carbonyl you're going to switch the locations of a pi bond and a hydrogen, okay? So, what winds up happening is that the hydrogen jumps up to where the pi bond was and the pi bond jumps down to where the hydrogen was, okay? Now, the relationship between these molecules is called tautomers, okay? So, these are called tautomers to each other and just to be clear these are constitutional isomers of each other, right? there are constitutional isomers because atoms are moving. So, please don't call these resonance structures, right? Because resonance structures you can't move atoms, here you are moving atoms, okay? Like I said, this happens in aqueous environments and it happens specifically to ketones and aldehydes, okay? So, how does this work, okay? Oh, actually and then the two tautomers have names, I'm sorry, I forgot to tell you that, so the tautomer that normally looks like a carbonyl is called the keto tautomer, okay? Now, what's funny is that it's called the keto tautomer even if it's not a ketone. So, if it's an aldehyde you would still call it the keto tautomer, okay? Once you tautomerize what you're going to make is an alcohol on a double bond of vinyl alcohol, okay? Vinyl alcohols are special guys, because vinyl alcohols can tautomerize, okay? So, because you have a vinyl alcohol, this is called the enol tautomer, okay? Because you got alcohol directly attached to a double bond, en, enol, alright? So, you've got keto tautomer, you got enol tautomer, these are in equilibrium with each other in aqueous environments.
So, let's look at the acid catalyzed mechanism of how this happens, okay? So, in an acid environment, what we're going to do is are in a protonate first, okay? That's going to give me carbonyl that now has a positive charge and what can happen is that the conjugate base of the acid can wind up deprotonating an alpha proton, okay? I'm going to put the Alpha down here actually, an alpha proton. So, what happens is that it deprotonates the Alpha, makes a double bond and kicks the electrons up to the OH, okay? This makes the enol tautomer, okay? So, I have an enol one side, I have a keto one another and I used acid to make this exchange happen, okay? So, guys from now on, this is revolutionary, anytime that you see a ketone or an aldehyde you need to be thinking about tautomerization because this happens whether you like it or not, it's going to happen, okay? Let's look at the base catalyzed version, in a base catalyzed mechanism, we go straight for the Alpha proton right away. So, we're going to take my O negative, we're going to remove the alpha proton, we're going to make the double bond and kick up the electrons to the O, this is going to give us a negatively charged enol or a very special intermediate called an enolate anion, okay? That makes sense because it's the negatively charged version of enol. So, it's enolate, okay? There is an entire branch of chemistry around enolates and we're going to spend a lot of time dealing with enolates this semester, okay? They're very special, because of that we're going to go through the base catalyzed mechanism very often, because we want to achieve the enolate, the enolate, okay? Then to protonate, we would just use the conjugate acid and this would give us the enol, okay? So, once again, we have Keto, we have enol, the biggest difference with this one being that with a base catalyzed mechanism you pass through this intermediate, that's actually very reactive and very important, okay? So, base catalyzed gives you an enolate and that's what tautomerization is, this helps to explain the acidity guys because the reason that that alpha carbon is so acidic with a pKa of 20 is because you can form a stable conjugate base or a stable molecule if you remove it, because you can always just form the enol, alright? Awesome, let's move on to the next video.
Give the important resonance forms for the possible enolate ions of:
In a strongly acidic solution, cyclohexa-1,4-diene tautomerizes to cyclohexa-1,3-diene. Propose a mechanism for this rearrangement, and explain why it is energetically favorable.
Draw guanine and cytosine in the enol form.
When a dilute solution of acetaldehyde in D2O containing NaOD is shaken, explain why the methyl hydrogens are exchanged with deuterium but the hydrogen attached to the carbonyl carbon is not.
Explain why a proton can be removed from the α-carbon of N, N-dimethylethanamide but not from the α-carbon of either N-methyl ethanamide or ethanamide.
The following reaction process is an example of
Consider each of the equilibria shown below. Does the equilibrium lie to the left or to the right?
Identify the keto form of the following enol.
Which of the following is not correct?
a Tautomerization is catalyzed by both acids and bases.
b Tautomers are constitutional isomers.
c Tautomers rapidly interconvert.
d The enol form is generally more stable.
e All of the above are correct with respect to tautomers.
How many α-hydrogens does 2-hexanone have?
Refer to the reaction drawn below to answer the following questions.
In the presence of acid or a base a ketone can be converted into an ___________. This process is called
The ketone predominates because _______________________________________________________.
Which represents a keto-enol tautomerization?
Estimate Keq for the following reaction and explain if the equilibrium favors the reactants or the products.
pKa α-H cyclohexanone 20; pKa HCN 9; pKa β-H cyclohexanone 40
Write out the mechanism for the following transformation.
Write out the mechanism for the following transformation.
The final step in the hydration of an alkyne under both acidic and basic conditions is the tautomerization of an enol intermediate to give the corresponding carbonyl. Provide an arrow-pushing mechanism for the tautomerization under acidic conditions.
How many tautomers can you draw?
How many acidic protons (pKa ≤ 20) are in the following compound?
Draw the enol tautomer for the following ketone:
Consider the structural formula of acetaldehyde below.
(a) Give a chemical equation for the reaction between hydroxide ion (HO -) and acetaldehyde in which HO- acts as a Lewis base and acetaldehyde acts as a Lewis acid. IMPORTANT: The Lewis base that you give cannot be a Bronsted-Lowry base; the Lewis acid that you give cannot be a Bronsted-Lowry acid. Note: Use Lewis structures for each reactant/product and use curved arrows appropriately.
(b) Using Lewis structures for each reactant and each product and using curved arrows appropriately to show the flow of electrons in the reactants, give a chemical equation for the reaction between hydroxide ion (HO -) and acetaldehyde in which HO- acts as a Bronsted-Lowry base and acetaldehyde acts as a Bronsted-Lowry acid. Do not give the same answer that you gave in the first part of this question.
Which of the following is (are) a keto-enol tautomeric pair(s)?
Tautomerization is the name given to the process by which keto and enol forms interconvert. The keto and enol forms are constitutional isomers that reach an equilibrium in acidic or basic conditions.
Tautomerization is possible in both acidic and basic solution. Let’s look at the mechanisms to go from ketone to enol and back to ketone. The keto form is the familiar carbonyl, while the enol form is basically a vinyl alcohol.
The first step in the acidic mechanism is protonation. Heads up: H3O+ is the same thing as H2O and H+. Once the protonated carbonyl is formed, the conjugate base will remove the acidic alpha hydrogen. This forms a bond between the carbonyl carbon and the alpha carbon, and the carbonyl’s pi-electrons are kicked onto the oxygen to form the enol.
To go back to the keto form the oxygen reforms the carbonyl, and the C=C bond’s pi-electrons deprotonate the H3O+ to form H2O again. Then the water removes the proton from the oxygen and voila! You’ve got nice C-C and C=O bonds again.
The base-catalyzed mechanism starts with the deprotonation of the alpha carbon by a base like –OH. This deprotonated enol is called an enolate, and it’s found extensively in condensation reactions. The anionic oxygen grabs the hydrogen from the conjugate acid, and now we’ve got ourselves an enol.
To go back to the keto form, the alcohol is deprotonated. Then the anionic oxygen kicks a lone pair down to reform the carbonyl, and the C=C bond’s pi-electrons are used to deprotonate the H2O to form –OH again.
In general, the keto form predominates in equilibrium because it is lower in energy. You can even think about this in terms of an acid-base reaction. Equilibrium direction goes from more acidic to less acidic, so it makes sense that the equilibrium would favor the keto form. An alpha hydrogen’s pka is about 20, and an alcohol’s pka is about 16. The alcohol is about ten thousand times as acidic as the alpha carbon.
The equilibrium of beta dicarbonyls will actually shift toward the enol form. Why? The enol form is conjugated from one oxygen to the other though the c-c pi-bond, and it also has that hydrogen attached to one of the oxygens which results in hydrogen bonding to the other oxygen.
Imines and enamines can actually tautomerize just like ketones and enols. Imine-enamine tautomerization actually plays a pretty big role in enamine alkylation through the Stork enamine mechanism.
P.S. Sometimes tautomerization can occur in DNA base pairs. Normally guanine pairs with cytosine, but the enol form of guanine will actually pair with thymine. Just another way Genetics can get pretty complicated.
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