Carboxylic Acid Derivatives
Last updated: January 25th, 2023 |
- All acid-base reactions are technically proton transfers, where a bond to H+ breaks, and a bond to H+ forms.
- However, the term “proton transfer” is often used to describe processes where a proton (H+) moves from one part of a molecule to another. Like this:
- There are two general ways of drawing the mechanism for proton transfer reactions.
- The most correct way is to use a molecule like H2O that can serve as a “proton shuttle”. The proton transfer mechanism can then be shown via two consecutive acid-base reactions. (Protonation-Deprotonation or Deprotonation-Protonation ; when drawing these mechanisms, make sure to avoid making molecules that have a net charge of +2 or -2 !)
- Alternatively, proton transfer can be drawn as an intramolecular process. This is most likely when a relatively unstrained 5- or 6-membered transition state can be drawn.
Proton transfer is a key step in many reactions of neutral nucleophiles with carbonyl compounds, and often precedes elimination of a leaving group. (See post: Addition-Elimination Mechanisms of Neutral Nucleophiles)
Table of Contents
- What Is “Proton Transfer”?
- The Two-Step “Never-Fail” Mechanism For Most Proton Transfer Reactions
- A Tempting (But Generally Wrong) Mechanism For Proton Transfer
- Proton Transfer Under Neutral Conditions
- Proton Transfer Under Basic Conditions (e.g. Enolates)
- Intramolecular Proton Transfer Reactions Can Sometimes Be OK
- The Magic Wand of Proton Transfer
- Quiz Yourself!
- (Advanced) References and Further Reading
All acid-base reactions involve the formation and breakage of a bond to a proton (H+). So all acid-base reactions are technically “proton transfer” reactions.
However, the term “proton transfer” is often used to refer to processes like this one.
In this specific reaction a bond to H+ is formed (N-H), and a bond to H+ is broken (O-H).
These processes often occur in the reactions of the carbonyl group. Since the conjugate acid is a better leaving group, a proton transfer often precedes an elimination step. [See post: Carbonyl Mechanisms – Addition-Elimination]
In this article, I’ll briefly show a simple, two-step never-fail “proton shuttle” mechanism for drawing proton transfer in the section below.
Then I’ll show another example of how not to draw the mechanism.
Then we’ll go over examples of proton transfer under neutral and basic conditions.
I’ll finish up with drawing a time saving “cheat” that you will inevitably use if you ever take advanced courses in organic chemistry.
In 90% of the cases where you will be asked to draw the mechanism of a proton transfer it will involve a positively charged starting material going to a positively charged product. (This generally happens under acidic conditions)
Any mechanism for this reaction has to show breakage of O-H and formation of O-H. In other words, one atom undergoes protonation and another undergoes deprotonation.
There are two common ways to draw this mechanism.
- As a series of two intermolecular acid-base reactions starting with a weak base ” B: ” (specific examples of “B: ” include water or alcohols)
- As a single intramolecular step (not recommended)
If you are asked to draw this mechanism I strongly recommend using the following two-step mechanism. [Note 1]
In the first step, a weak base (such as water, H2O) acts as a base, breaking O-H and resulting in a neutral species.
The second step of the proton-transfer mechanism is to use the resulting acid (e.g.) H3O+ to form the desired bond to H.
Together, these two steps (Deprotonation – Protonation) have resulted in the movement of a proton from one atom to another.
That’s it. Proton transfer accomplished!
Note how our weak base (e.g. H2O) helps to transport the proton from one atom to another. For this reason the weak base in this reaction is often called a “proton shuttle“.
An alternative two-step mechanism is shown below involving Protonation – Deprotonation.
Do you think this is a reasonable alternative? Why or why not?
I’ve never personally seen the two-step proton shuttle mechanism marked as “wrong” on an exam.
For that reason I pretty much guarantee that you will not be penalized for writing out a proton transfer mechanism in this way.
I can’t say the same thing for the intramolecular mechanism below, however:
Let’s just acknowledge that drawing the proton transfer in this way is very tempting. First of all, drawing this mechanism only requires two arrows instead of four, and happens in one step instead of two.
Secondly,the base is soooo close to the proton. I mean, it’s right there. What’s not to like?
Be warned, however. It is also the kind of mechanism that many instructors will frown on because it involves a 4-membered transition state.
A four-membered transition state would involve some less-than-ideal geometry and bond angles in the atoms undergoing the proton transfer. A transition state where C-O-H adopts a bond angle of around 90° (as opposed to the preferred near-tetrahedral angle of around 107°) is going to be energetically unfavorable.
For this reason, if you draw the mechanism this way, don’t be surprised if you get a slap on the wrist. But don’t trust me. Check with your instructor.
For what it’s worth, experimental evidence generally does not support the intramolecular mechanism in these cases. [Note 2]
The above section covers 90% of the proton transfer mechanisms you’re likely to see. But for completeness we should round out the discussion with some examples of proton transfers under neutral and basic conditions.
Let’s look at proton transfer under neutral conditions first.
The first step is nucleophilic addition of the alcohol to the ketone. This results in the formation of a new species which possesses both a negative and positive charge. This doubly charged species with no net charge is referred to as a zwitterion.
To get to our neutral hemiacetal a proton transfer must occur.
How do we best draw the proton transfer mechanism in this case?
Again, I strongly recommend drawing this as a two-step process.
- In the first step, we could use a molecule of the alcohol to deprotonate OH2 to give OH.
- We could then protonate the O(-) with the resulting ROH2(+) to give OH.
There is also a second, completely valid way to draw the mechanism.
See if you can draw mechanisms for these cases
A third category of proton transfer reactions are those where a proton is transferred under basic conditions.
In this case the first step is generally protonation followed by deprotonation.
See if you can draw this proton transfer using H2O as a proton shuttle.
As noted in the quiz, the wrong way to do it would be to deprotonate first, since this would result in a di-anion (unstable!).
Proton transfer under basic conditions comes up from time to time in important mechanisms.
One specific example is found in the Robinson annulation reaction (See post: The Robinson Annulation) which contains a step where a negatively charged species (an enolate) is transformed into a different enolate.
(These are not resonance forms!)
In this reaction C-H is broken and C-H is formed.
The order in which these steps should occur is 1) Protonation 2) Deprotonation.
One way to show this proton transfer would be with H2O as a proton shuttle (assuming NaOH was used as base).
This is another case where drawing an intramolecular proton transfer would be very bad since it would again involve a four-membered transition state.
There is also a way to show the proton transfer here without any involvement by H2O. See this quiz for an example.
As noted previously, drawing intramolecular proton transfers is generally not something I recommend. However, if proton transfer involves a relatively unstrained cyclic transition state (say, 5- membered or above) then drawing a concerted intramolecular transition state is fine.
These are perfectly acceptable proton transfer reactions, for example.
The two-step mechanism is also valid
Ultimately. proton transfer is one of those very mundane reactions that isn’t very interesting.
It’s quite possibly the least sexy reaction in organic chemistry.
It can occur via multiple paths. Many equivalent mechanisms can be drawn depending on what molecule you choose as a proton shuttle.
Furthermore detailed studies on proton transfer mechanisms indicate it is even more complicated than what I have described here. [Note 2]
It’s a lot of work for what is essentially a very boring reaction. Nobody really cares how it happens. You just want to transfer the damn proton and move on with your life.
For that reason, once students reach a certain assumed level of competence, you may notice instructors (and teaching assistants) will start to just draw proton transfer in the following way.
You just write “proton transfer” (or better yet, “PT” ) and be done with it.
Then you move on to more interesting parts of the mechanism.
I fondly refer to this as the magic wand of proton transfer.
If you’re drawing proton transfer, there are just a few things to keep in mind:
- Avoid drawing intermediates that have multiple charges (no di-cations or di-anions! )
- Avoid drawing strained 3- or 4-membered rings for intramolecular proton transfer (avoid ring strain)
- Use a weak base present in solution as a “proton shuttle“
In many cases, especially in the reactions of aldehydes and ketones, a proton transfer step generally precedes an elimination step.
The common “PADPED” pattern (Protonation-Addition-Deprotonation-Protonation-Elimination-Deprotonation) that applies to a large number of carboxylic acid derivatives has a proton transfer (D – P for Deprotonation-Protonation) right before the Elimination step.)
See the post on the PADPED pattern for more (See article: Making Music With Mechanisms – PADPED)
Note 2. A study on the mechanism of the hydration and dehydration of ketones indicated that the most likely mechanism for the proton transfer step involved a transition state incorporating two or three equivalents of water, like this [Ref]
For our purposes, however, the two step “proton shuttle” mechanism is fine. It’s an oversimplification, but an oversimplification we can live with.
Proton Transfer Reactions edited by E.F. Caldin and V. Gold (Chapman and Hall, 1975) was extremely useful in finding references on the mechanism of proton transfer reactions, particularly chapter 11.
Another classic reference is The Proton In Chemistry by R. P. Bell.
- The Acid-Base-Catalyzed Mutarotation of α-D-Tetramethylglucose in Mixed H2O-D2O Solvents1
H. H. Huang, R. R. Robinson, and F. A. Long
Journal of the American Chemical Society 1966 88 (9), 1866-187
The authors measure the rate of mutarotation (which involves proton transfer via hemiacetal formation/cleavage) and measure the rate constants for reactions in D2O and H2O with 4 different catalysts. Based on this data, a transition state with two to three solvent molecules of H2O is proposed for the proton transfer step.
- Kinetics of Proton Transfer Processes
Discuss. Faraday Soc., 1965,39, 7-15
Proposes a transition state for hydration containing two or more water molecules in a concerted process involving a hydrogen-bonded transition state, since estimates of the absolute rates of individual, stepwise acid-base reactions led to impossibly high rate constants in certain cases.
- Kinetics of the reversible hydration of 1,3-dichloroacetone in dioxane and acetonitrile solution
Ronald Percy Bell, J. P. Millington and Judith M. Pink
Proceedings of the Royal Society A 1968, 303, 1-16
Study on the mechanism of hydration of 1,3-dichloroacetone, proposes that: “…the uncatalyzed hydration reaction takes place with the cooperation of three water molecules, one or two of which can be replaced with a catalyst molecule”.
- Intramolecular Catalysis in the hydrolysis of glycosides and acetals
B. Capon, M.C. Smith et. al.
J. Chem. Soc. B. 1969, 1038-1047
Example of an acetal hydrolysis reaction where the rate is greatly accelerated due to an intramolecular proton transfer.