Nucleophilic Reaction

Nucleophilic Reaction

There is no denying the fact that when we study nucleophilic substitution and elimination reactions, we find that learners typically have very little trouble drawing each mechanism and predicting the products, so long as they are specifically told which reaction. But many learners find one aspect very challenging: predicting the winner of an S_N1/S_N2/E1/E2 competition. In our studies, The SN1/SN2/E1/E2-competition exam was the exam where many pre-health learners decided that their fate was sealed. In the years since then we have turned things around considerably. What did We learn? And what did We change?

This most important thing we learned was why learners were struggling with predicting which reaction dominates—learners were memorizing! We initially thought it was strange that learners were memorizing because we felt that the textbook we are using clearly explained the various factors that favor one reaction over another; and we heavily reinforced those ideas in class. But then it became apparent to me why learners still resorted to memorization. After treating each of those factors separately, the textbook we are using brought them together to summarize and make generalizations about the competition, as well as to provide exceptions. For example, if (1) the attacking species is both a strong nucleophile and a strong base, and (2) the substrate is primary, then SN2 will give the major product and E2 will give the minor product. An exception is when the attacking species is the tert-butoxide anion, in which case E2 will give the major product and SN2 will give the minor. As another example, if (1) the attacking species is a strong nucleophile but a weak base, and (2) the substrate is secondary, then both SN1 and SN2 can occur. In an aprotic solvent, however, we can expect SN2 to dominate.  But if the substrate is benzylic, the solvent is protic, and the leaving group is very good, then we can expect SN1 to dominate.

Not surprisingly, when a student sees that 15 pages of chemistry has been distilled down to a single page (or a single table) of summary/generalizations, it is incredibly attractive to try to memorize them. There are two major problems that arise. One is that, by doing so, learners circumvent the actual chemistry, so there ends up being no context for why a particular reaction dominates. This makes it easy for a student to forget a critical piece of information or become confused, especially given the large number of different combinations in which the factors can contribute. The second problem is that, in addition to memorizing the general rules, learners must also remember which scenarios require additional information, such as when to consider solvent, the bulkiness of the attacking species, or the benzylic nature of the substrate. In other words, learners feel that they must memorize exceptions in addition to the rules.

I’ve since had a huge effect on my learners’ success with the SN1/SN2/E1/E2 competition by providing a system for deciding the winner of the competition, which consists of the following steps:

(1)  Determine if the leaving group on the substrate is at least as good as F−. If so, then

(2)  Examine the type of carbon to which the leaving group is attached.

1. If the carbon is primary, then rule out SN1 and E1 unless the carbocation can be resonance-stabilized.
2. If the carbon is tertiary, then rule out SN2.

This system is also incorporated into my new textbook for two reasons. First, it gives learners something to hang their hat on. Yes, learners must still remember how to execute these steps, but the system for doing so does not change from one scenario to the next. The second great benefit is that when going through these steps, learners will frequently be reminded why. When deciding whether a leaving group is at least as good as F−, for example, they must apply arguments of charge stability. When the carbon is tertiary, which rules out SN2, learners will be reminded that it is due to steric hindrance. And it is this type of reinforcement that sets learners up for being in command of other reactions they will encounter in the course.

1. What do you mean by a leaving group “as good as F-“? What about OH- leaving group?
2. What do you mean by the “concentration of the attacking species”?
3. Also, doesn’t it matter if the attacking species is a good Nu or a good base? Or both? WEknow that something that is just a good base will only favor certain reactions. I’m still a little confused by which ones are good Nu’s, bases or both and if those are things we should just memorize…

1. A leaving group “as good as F-” essentially has to do with charge stability of the leaving group in the form in which it comes off. Cl-, for example, is a much better leaving group than F- because, being a larger atom, chlorine can better handle the charge. H2O is also a much better leaving group than F- because it is uncharged. HO- is a worse leaving group than F- because O is not as electronegative as F, meaning that the negative charge cannot be accommodated as well. There is also a nice correlation between how good a leaving group is and the pKa of its conjugate acid: The stronger the conjugate acid, the better the leaving group is. The pKa of HF, for example, is around 3 and the pKa of HCl is around -7. HCl is a much stronger acid than HF, so Cl- is a better leaving group than F-.

2. The attacking species is the species that can act either as a nucleophile or as a base. In short, the higher the concentration of the attacking species, the more that SN2 and E2 reactions are favored in the competition, whereas the lower the concentration of the attacking species, the more that SN1 and E1 reactions are favored. This can be understood from the rate laws of the respective reactions, but We like to add a more qualitative argument to the picture, which goes something like this: In an SN2 or E2 reaction, the attacking species is responsible for “forcing off” the leaving group (either directly or indirectly). Therefore, the greater the number of attacking species, the better that job can be accomplished. In an SN1 or E1 reaction, on the other hand, the attacking species must wait for the leaving group to have come off. Therefore, increasing the number of attacking species just means that there are more of them waiting.

3. We think this question relates very closely to the qualitative picture in #2 above. Strong nucleophiles favor SN2 over SN1 because they are good at forcing off the leaving group. Strong bases favor E2 over E1 for the same reason. An attacking species like HO-, for example, is a strong nucleophile and a strong base, so it tends to favor both SN2 and E2 over SN1 and E1. Cl-, on the other hand, is a strong nucleophile but a weak base, so it tends to favor SN2 over SN1 (strong nucleophile), but favors E1 over E2 (weak base). Now, identifying an attacking species as a strong base or strong nucleophile is important. There’s a bit more to it than this, but basically, strong nucleophiles tend to have a full negative charge, and strong bases are ones that are roughly as strong as HO- or stronger.