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The Most Annoying Exceptions in Org 1 (Part 2)

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?


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