Carboxylic Acid Derivatives
By James Ashenhurst
How Reactions Are Like Music
Last updated: May 21st, 2019
One of the joys of this video is watching the reactions of the audience as it is revealed that song after familar song – from “Don’t Stop Believin'” to “Waltzing Matilda” – is built on the same four chords. It also got me to thinking – what analogies exist between music and organic chemistry?
Here’s a fanciful analogy I’m playing with: reactions are like music.
Most pop songs are built up from chords. I’m no musician, but I believe there are something like 6 major and 6 minor chords (plus a lot of little variations on them, like suspended 5ths and things like that): these chords are the building blocks of most of the songs we recognize from the radio.
Reactions are built up from individual mechanistic steps. These are the indivisible building blocks (or elements, if you will) of organic reactions. In carbonyl chemistry, which is what I’ve been writing about for the past month and a half, there are 6 mechanistic steps that we’ve talked about plus another 2 that make an appearance in dehydrations like the acid-catalyzed Aldol.
Here are the building blocks of carbonyl reactions:
- Protonation and deprotonation.
- [1,2]-addition and [1,2]-elimination
- [1,4]-addition and [1,4]-elimination
- The SN2
That’s 8 different elements, 9 if you count proton transfer as distinct (I tend to, although it’s just a net intramolecular acid-base reaction).
So if each of these steps is like a chord, what would the songs look like?
“Songs of the Carbonyls “
(not meant to be comprehensive BTW)
2 chord songs:
- All the simple addition reactions of negatively charged nucleophiles with aldehydes/ketones: e.g. alkoxide addition, cyanohydrin formation with CN(–), addition of Grignards, simple reductions (e.g. NaBH4): [1,2]-addition + protonation (quench)
- Reactions of neutral nucleophiles with aldehydes/ketones: addition of water, alcohols, or amines: [1,2]-addition + proton transfer
- [1,4]-additions of anionic nucleophiles to enones: addition of organocuprates, NR2(–), RO(–), CN(–), etc. [1,4]-addition + protonation
- [1,4]-additions of neutral nucleophiles to enones: addition of amines, enamines to enones. [1,4]-addition + proton transfer
- Hydrolysis of acid halides with anionic nucleophiles: e.g. reaction of OH(–) or NR2(–), etc. [1,2]-addition + [1,2]-elimination
- Enolate alkylation: deprotonation + SN2
- The Aldol Reaction (base-catalyzed): deprotonation (to make enolate) + [1,2]-addition + protonation
- The Michael Reaction: deprotonation + [1,2]-addition + protonation
- The Claisen condensation: deprotonation + [1,2]-addition + [1,2]-elimination
- Acid-catalyzed additions of nucleophiles to aldehydes/ketones: e.g. acid-catalyzed hemiacetal formation (alcohol + aldehyde/ketone), acid catalyzed cyanohydrin formation, etc. protonation + [1,2]-addition + deprotonation
4 chord songs:
- The acid-catalyzed Aldol : protonation + tautomerization + [1,2]-addition + deprotonation
- ‘Reaction of acid chlorides with neutral nucleophiles (e.g. water, amines): [1,2]-addition + proton transfer + [1,2]-elimination + deprotonation. (see this post)
- The Fischer esterification, ester hydrolysis, amide hydrolysis, imine formation: protonation + [1,2]-addition + proton transfer + [1,2]-elimination + deprotonation . This is the “Don’t Stop Believin’ ” of carbonyl reaction mechanisms. Those 4 reactions might look different on paper, but they all share the same mechanistic pathway.
- Reaction of Grignards with esters/acid halides: [1,2]-addition + [1,2]-elimination + [1,2]-addition + [1,2]-elimination + protonaion (to give the tertiary alcohol).
- Acetal formation: protonation + [1,2]-addition + proton transfer + [1,2]-elimination + [1,2]-addition + deprotonation. Similar to “Don’t Stop Believin'”, above, but with an extra [1,2]-elimination step thrown in.
- Acid-catalyzed Aldol dehydration: protonation (of first component) + tautomerization (of second component, to form enol) + [1,2]-addition + proton transfer + enolization + [1,4]-elimination + deprotonation
Here’s an idea for silly avant-garde art project. It would be a fun exercise to actually assign real chords to each of the 8 steps (9 counting proton transfer) and see if there’s some kind of internally consistent arrangement that makes these “Songs of the Carbonyls” sound any good.
It’s nice to imagine that they would be possessed of a haunting beauty that underscores the harmony implicit in the flow of electrons from nucleophile to electrophile.
Alas, I regard it as more likely that the songs would be more useful for annoying your dog than anything else.
I am kind of curious to see if transcribing these patterns into a musical format would help to get across the essential structure of chemical reaction pathways. Imagine if music could be used a trigger for remembering reaction mechanisms!
This discussion would not be complete without mentioning Alexander Borodin, the Russian chemist who was a co-discoverer of the Aldol reaction and a well-known composer in his day. His music is still played: some of it is on Youtube. It is very pleasant. Perfect for a quiet Saturday afternoon.
Final note: the delightful (but sadly quiescent) chemistry blog A Synthetic Environment has a link on 5 famous musician chemists.