By James Ashenhurst
Summary Sheet #3: Reactions of Carbonyls – The Big Picture
Last updated: March 26th, 2019
The reason why I harp on organic chemistry as boiling down to “nucleophile attacks electrophile” is because it’s a greatly simplifying way to look at chemical reactions. After you’ve done organic synthesis for awhile, you start looking at functional groups like they were really complicated pieces of Lego: while their shape, size, and colour may be different, the principles which govern how they fit together are the same. The way I look at it, nucleophiles are like the little nubby bits that stick out of the top of the blocks, and electrophiles are the empty spaces on the bottom which they fit into.
To make this point in exhaustive detail, here is a sheet I put together detailing many of the most well-known reactions in carbonyl chemistry. It’s set up in a grid, with nucleophiles on the X axis (in blue) and electrophiles on the Y axis (in red). On the table there are a total of 11 classes of nucleophiles and 10 classes of electrophiles, for a total of 110 different combinations. (Carbonyls_Big_Picture PDF.)
Looking at it, I think people find organic chemistry really hard is because there is such a huge variety of combinations of reactants. If you find that this sheet fries your eyeballs and your brain with the heat of a thousand suns, step back for awhile and take the time to understand the trends first. The axes are arranged in approximate order of reactivity, with the most reactive species at the top left (aldehydes, Grignards, A and 1, respectively) and the less reactive species at bottom, right (acetals, water, H and 9 – NaBH4 and LiAlH4 are 10 and 11 because I wasn’t sure where else to put them). Understand the trends that dictate carbonyl reactivity and nucleophile reactivity first before trying to memorize details. For your reference, the two summary sheets I previously put together on carbonyl chemistry are here and here. The two posts I put together on “Carbonyl chemistry – 10 key concepts” are here and here. I think that trying to memorize each of the different 110 combinations is nuts. First of all, they’re not all equally important, and secondly, it kind of misses the point of the exercise. It’s like memorizing multiplication tables without being able to do arithmetic. The point of putting together this sheet is to help people understand the principles of how chemical reactions happen, and to help to visualize the patterns.
I think one of the key simplifying observations from this table is that when you boil it all down there are only 5 – yes – 5 – reactions you need to understand thoroughly. Every single one of the 110 cells represents a sequence of one or more of these reactions. These are the individual components of each reaction mechanism. If you’re feeling lost or overwhelmed, I advise you to get these 5 reactions straight first. They are at the heart of carbonyl chemistry (and a lot of other organic chemistry, for that matter).
The five reactions are: 1) protonation/deprotonation 2) 1,2-addition (addition to carbonyls) 3) 1,2-elimination (the reverse of 2). 4) 1,4 addition (addition to enones) 5) SN2 (e.g. enolate alkylation). I suppose if you want to be picky you can say that elimination to form enones (e.g. in the Knovenagel and in the aldol condensation reaction) represents a different mechanistic pathway from 1,2-elimination. OK fine. So those cells represent reaction #6. For the other 108 you only need 5.
The other key thing to understand is the relative reactivity of functional groups, which you can learn more about by spending some time with a quality pKa table (this will give you information about the relative basicity of different functional groups, as well as leaving group abilities) and also to understand the relative π donation abilities of different functional groups (this you can obtain from the chapter in your textbook on electrophilic aromatic substitution).
I think this is a valuable sheet, and I hope you will agree. I know something like this would have really helped me when I was taking Org II: it’s basically a reactivity map. Putting this together was fun for me. Let me know if there are any mistakes or it needs improvement.