Carboxylic Acid Derivatives
By James Ashenhurst
Carbonyl Mechanisms: Neutral Nucleophiles, Part 1
Last updated: March 26th, 2019
Today, building on the previous 2-part series on mechanisms of anionic nucleophiles in carbonyl chemistry, I’m going to start looking at the reactions of the neutral nucleophiles: water, alcohols, amines, enols and enamines, using this chart as our guide. I think it’s fun to take something complicated and break it down logically into smaller, simpler components. The goal here is that by the end, it will hopefully be more clear how a monster mechanism like the acid-catalyzed aldol reaction (with 7 distinct steps!) is made up a small, finite number of little understandable parts. But before we get there, we’re going to start with the simplest cases: the 2-step reaction mechanisms of neutral nucleophiles.
Like anionic nucleophiles, all the reactions of these species can be described using a handful of components, or mechanistic “parts”. They are: 1,2-addition, 1,2-elimination, 1,4-addition, 1,4-elimination, the SN2, protonation/deprotonation, and enolization.
The main difference between the mechanisms of reactions of neutral nucleophiles and those of the anionic nucleophiles is the fact that there is a LOT of proton shuffling steps, as we’ll see.
Today I want to get across two main points.
The first main point is this: when a neutral nucleophile attacks an electrophile, you obtain a POSITIVELY charged compound. Let’s look at the general case and then a specific case.
If you calculate the formal charge in these reactions you’ll see that it’s always +1.
This is in contrast to the reactions of negatively charged nucleophiles, which always react with electrophiles to give neutral products.
What are the consequences of this? Well, this brings up the second important point. In 99% of the reactions in this class, the product you care about is going to be NEUTRAL. In contrast to negatively charged nucleophiles, which can give you one-step reaction mechanisms (example: SN2 of sodium methoxide with methyl iodide to give dimethyl ether), with neutral nucleophiles you’re going to have to do a SECOND reaction that involves removing the positive charge at some point. So the minimum number of steps you can have in the reactions of neutral nucleophiles with electrophiles is going to be TWO.
Let’s look at these two-step reactions first. They include the simple addition reactions of neutral nucleophiles to carbonyls, alkyl halides, and to α,β unsaturated ketones. (I picked an alcohol, an enamine, and an amine for the three respective reactions but I could have changed the order around and it wouldn’t matter: the principles are the same.)
The first step is the reaction of the nucleophile with the electrophile to produce a charged intermediate. The mechanisms of these reactions are all the same as they are for the reactions of the negatively charged nucleophiles.
The second step is an acid-base reaction. You’ll notice that for the 1,2 and the 1,4 additions, the reaction intermediate is a zwitterion (contains a positive and a negative charge). So it’s possible to neutralize the molecule by doing the reaction we just call “proton transfer”. You can draw it as two intermolecular acid-base reactions, or you can draw it as an INTERNAL acid-base reaction. Or… you can just take out your magic wand and write “proton transfer” over the arrow, because it can happen by either pathway and it’s relatively unimportant how it occurs.
The SN2 reaction produces a charged intermediate that needs to be neutralized by an external base [in this example we’ve generated one equivalent of HI]. By the way, this is pretty important – when you are adding a neutral nucleophile to an alkyl halide in the lab, you generally need to add extra base (like pyridine for instance) to mop up the extra acid, otherwise the reaction will stall on you.
So these are the simplest reaction mechanisms you’ll see for neutral nucleophiles: addition, then an acid-base reaction. Next time I’ll talk about the THREE-step reaction mechanisms in carbonyl chemistry.
Final note – if there’s something that’s unclear, yell at me in the comments!