Fun and Miscellaneous
The Most Annoying Exceptions in Org 1 (Part 2)
Last updated: May 24th, 2021 |
Last time we talked about how some interesting electronic effects can lead to unexpected results in organic chemistry. Today we look at three examples of how steric factors can lead to unexpected products (or lack of products). The last example is a case where both steric and electronic factors can be dominant, depending on the situation.
Annoying exception #5 – bulky bases. Under normal conditions, we’re taught that eliminations always favor the more substituted alkene (Zaitsev’s rule) because they are more thermodynamically stable. However, when a bulky base is used (t-butoxide or LDA) we observe that the major products instead result from removal of a proton at the least hindered carbon (Hofmann Product).
The key lesson here is that steric effects are destabilizing, and the transition state leading to the Zaitsev product is necessarily going to be the most sterically hindered. If a bulky base is used, the destabilizing steric effects of the Zaitsev transition state start to outweigh the stabilizing effect of forming the more substituted double bond, and the Hofmann transition state is favored.
Annoying exception #6 – the Hofmann Elimination. Here, in the reaction that gives the “Hofmann” product its name, is another example of how extreme steric effects can outweigh greater thermodynamic stability of the product. When an extremely bulky leaving group is present (NR3(+) being the prominent example) the Hofmann transition state becomes favored due to the destabilizing gauche interactions present in the Zaitsev transition state.
Annoying exception #7 – the neopentyl group. We’re all taught that primary alkyl halides are great substrates in the SN2 reaction. However, the neopentyl group (t-butylmethyl) is a prominent exception. When you compare the reaction rates of propyl halides with neopentyl halides, the rate for the propyl halide is about 100,000 times faster. For practical purposes, neopentyl halides are inert in the SN2.
. We’re familiar with the fact that the SN2 is sensitive to steric hindrance and therefore as we increase steric bulk on the carbon bearing the leaving group (i.e. the alpha carbon) the rate will decrease. However, the key lesson here is that if the carbon *next to that* (i.e. the beta carbon) is bulky enough, it can start to have an impact too. In the case where the beta carbon is tert-butyl, the reaction shuts down almost completely.
Annoying exception #8 – the behavior of epoxides. Under basic conditions, nucleophiles attack epoxides at the least substituted carbon. Under acidic conditions, nucleophiles attack at the most substituted carbon. What’s going on here?
As you might suspect what’s happening here is that there is a switch between different mechanisms, both of which should be familiar by the end of Org 1. Under basic conditions, the nucleophile is attacking the less substituted carbon in a classic SN2 reaction. Under acidic conditions, however, the epoxide becomes protonated, and the resulting cation strongly resembles the brominium and mercurinium ions produced by the addition of Br2 and Hg(2+) to alkenes, respectively. In this situation, the nucleophile attacks the carbon atom best able to stabilize positive charge, which happens to be the most substituted carbon. Hence the different reactivity patterns.
Did I miss any other prominent annoying exceptions?
14 thoughts on “The Most Annoying Exceptions in Org 1 (Part 2)”
Another on: very poor leaving groups (as F-) lead to Hofmann products. The reason is due to electronic reasons (similar to what is happening electronically with quaternary ammonium leading to amine leaving group).
Excellent!. I agree with you: I wish such sites were present when i was beginning to learn chemistry way back when
Then what is the product formed when neopentyl bromide reacts with NaOH?? N whats the mechanism behind it?
Would just be neopentyl alcohol. SN2. Although the reaction would be pretty slow.
It seems the attempt to clear common Misconceptions is the main focus here.
I am an Indian student, preparing for my medical entrances. I have loved organic from the very beginning but somehow there were always some uncertanities in my mind while solving questions. You have cleared many of my concepts with your easy explanation which our professors fail to do. Thank you! God bless you.
These are not “exceptions” (parts 1 and 2). You create them by starting from wrong (or half-true) statements. It’s not didactic to explain things wrong and later complete the explanations calling them “exceptions”. Explain everything from the beginning, it’s less sensationalist, but people will understand it better. This is just a humble advice after having taught Organic Chemistry for 25 years.
Freshman orgo student here. Shouldn’t exception #8 be classified as an SN1 reaction? Or am I missing something here?
Thanks for commenting!
It’s similar, but not quite the same, as an SN1, because it does not go through a free carbocation. The difference is stereochemistry. In an SN1, there is both retention and inversion of stereochem. In the opening of epoxides under acidic conditions, there is only inversion. So it is ‘SN1-like’.
Hi James, that comment confused me a bit. How is there inversion in a Sn1 reaction? I thought inversion was specifically in Sn2 reactions.
On another note, really appreciate your awesome “breakdowns” of complicated mechanisms. Thank you for all your work!
Well, there’s “racemization”. So both (R) and (S) will form. One of those stereocenters will represent retention of configuration, the other will represent inversion.
So we will have a Hofmann elimination either a) use a bulky base or b) have a bulky leaving group. My book says that you need both?
There are two separate sets of conditions. a) bulky base, (e.g. NaOtBu) works with non bulky leaving groups to give “Hofmann” eliminations, as does b) a bulky leaving group (NR3) with a non-bulky base (eg. OH)
iPr groups on chairs.