Syllabus Review: There is no textbook for this class. I will post my notes online as soon as I have semicoherent notes available for posting.

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Jean Burns
7 years ago
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1 Class 1 Welcome: Welcome to organic chemistry 521. I had the privilege of teaching some of you last semester, and those people will be happy to know that this class and its grading scheme are going to be structured roughly the same way that chem. 427 was. Let s look at the syllabus and you ll see what I mean: Syllabus Review: There is no textbook for this class. I will post my notes online as soon as I have semicoherent notes available for posting. There will be three one hour tests. They are not technically cumulative, but understand that all of organic chemistry builds on previous discussions, and therefore I will feel free to ask about anything that I want. Each exam is 20% of your final grade. There is no final. There will be problem sets and problem set answers posted online. These will not be collected or graded. Additionally, each student will be required to write two briefs which summarize recent articles from journals such as J. Am. Chem. Soc. or Org. Lett. The briefs should be 3 to 5 pages long (1 margins, 12 pt. font, and 1.5 spacing), including figures. I will assign the first article to be summarized. For the second brief, each student will choose an article. Each brief will count for 10% of your final grade. The remaining 20% of your grade will be assigned based on class participation. You will only learn organic chemistry if you come to class and participate in the discussions. To that end, I will assign a daily participation grade from You will receive a minimum of a 7 for coming to class on time. You will be allowed four free or absentee days during the semester. For those of you who have taken Dr. Euler s class, my understanding is that he structures things similarly. Semester Overview: Now let s talk about what chemistry is going to be covered. We are going to divide the semester in three sub sections, which will conveniently coincide with your three scheduled tests. In the first third of the semester, we will cover standard physical organic chemistry topics. These include reaction mechanisms, carbocations, radicals, and other reaction intermediates. In the second third, we are going to talk in detail about some key organic reactions that may not have been covered (or covered only superficially) in some of your earlier chemistry classes. In the final third of the semester, we are going to talk in detail about some interesting total syntheses. I have office hours from 11 am noon on Tuesdays and Thursdays. I am always available by , or you can set up another appointment time that works for both of us. Demonstration Polymer in Hair Gel: We did this demonstration last semester, but I didn t have time to think of something new, plus at least I know this demonstration works. Anyone who can tell me a real (chemistry) explanation for what is going here will get 5 extra points on their first test. Stereochemistry of nucleophilic substitution reactions One main class of reactions in organic chemistry is nucleophilic displacement reactions, where a nucleophile replaces a leaving group on a molecule:

2 R R R LG + Nu - Nu R R R Nucleophile = something that loves a nucleus i.e. OH, SH There are also several examples of carbon nucleophiles, like CH 3 Li or CH 3 MgBr (organometallic compounds) This is contrast to electrophiles, which literally means something that loves electrons. There are two possible mechanisms of a nucleophilic substitution reaction: SN1 and SN2 (substitution nucleophilic unimolecular and substitution nucleophilic bimolecular). Everyone here should have learned that SN2 reactions proceed with backside attack (and inversion of stereochemistry), whereas SN1 reactions proceed via formation of a planar carbocation (that leads to equal attack from both faces of the intermediate): Mechanism of an SN2 reaction: Nu D A B C Nu D A B C Nu D A B Here the incoming nucleophile approaches from the backside (relative to leaving group C). You then form a five coordinate transition state, where both the nucleophile and the leaving group are partially bound to the carbon center, and then the leaving group leaves and you have a new compound. This should theoretically lead to 100% inversion of configuration. This new compound s stereochemistry has been inverted. Here is a real world SN2 reaction: Mechanism of an SN1 reaction:

3 Here the leaving group first leaves to generate a planar carbocation intermediate. By the time the incoming nucleophile sees this intermediate, both faces of the carbocation are identical, and the nucleophile has no preference for coming in from the top or bottom face. Therefore these reactions are expected to lead to a 50/50 mixture of inversion of configuration compared to retention of configuration. Again, just to reiterate SN2 reactions should lead to 100% inversion of configuration, and SN1 reactions should lead to 50% retention and 50% inversion. But real life is rarely so simple. Consider the following example: Is this reaction mechanism SN1 or SN2? Real life example 2: SN1 or SN2? In general I would like you to think that ANYTHING that gives a mixture of products is mostly SN1. The reason why you don t get a 50/50 mixture of the products is that once the leaving group departs, it often hangs around near the resulting carbocation. This partially blocks that face for attack by the incoming nucleophile, so that results in partial inversion. One more real life example that I hope you have seen (but will cover in any event) is neopentyl halides: Does this molecule undergo SN2 reactions?

4 Reasons why it would: It is a primary halide Reasons not to undergo SN2: It looks kind of hindered. Correct answer: It is too hindered to undergo the reaction! Let s look at the 3 d space filling model of this compound: Even though it is primary, consider it an exception to the rule that primary halides all undergo SN2. Understand that this is NOT a systematic discussion of SN1 and SN2 reactions. At this stage of your careers, I am assuming you have all covered this topic in some degree of detail. I will post some general review questions on your first problem set, but if it has been a while since you heard these terms, you may want to do some review on your own. Let s talk about a new (but related) topic called neighboring group participation. Definition of neighboring group participation: the involvement of nearby nucleophilic substituents in a substitution reaction. This means that whenever you look at mechanism or stereochemistry, you should really be considering all functional groups on the molecule to determine how they may affect the reactivity. Since I know that s kind of vague, let s look at a few real world examples: Compounds A and B are basically identical, except that they have different stereochemistry of the acetate group. However, when you treat them both with acetic acid and acetate (which does a substitution reaction on the tosylate group (OTs), you get two different outcomes. Compound A reacts

5 with retention of configuration, and compound B reacts with inversion of configuration. Also, compound A reacts 670 times faster than compound B under the same reaction conditions. What is going on here? It has to do with the neighboring acetate group. For compound A, the acetate group displaces the tosylate to generate a bicyclic intermediate and a more stable carbocation. This cation is particularly stabilized by three different resonance forms: In the next step, the acetate nucleophile comes in and does a backside attack on the top carbon atom to generate the product: So this is a two step process first the internal acetate displaces the tosylate, than that acetate is displaced by the external nucleophile. Each step is an SN2 reaction that proceeds with inversion of configuration, but because you have two steps, there is an overall retention of configuration observed. This explains pretty well what happens with compound A, but we still have not addressed the question of compound B. Why doesn t it behave similarly? That has to do with the geometry necessary for the neighboring group displacement. We can draw both compounds in the most stable chair conformations: We are operating under the assumption that these reactions proceed via SN2 mechanism and therefore require backside attack. When the two substituents are on opposite sides (as in compound A), that allows backside attack to take place. When the two substituents are on the same side (as in compound B), they cannot assume the right geometry for SN2 to occur and therefore the reaction does not take place. In the remaining time that we have, I would like to talk about leaving groups: There are three different sulfonate type leaving groups, shown below:

6 The best leaving group of these three is the triflate that is because leaving groups develop negative charge, so we need to look for the case where the negative charge will be most stabilized. Three highly electronegative fluorine atoms sufficiently stabilize the negative charge on triflate. After triflate, the next best leaving group is tosylate, because the negative charge can be partially delocalized over the phenyl ring. For mesylate, there is no place to delocalize the negative charge and therefore it is the worst leaving group of the three. A cautionary note when we talk about leaving groups in terms of electronegativity when you look at halides (and what kind of leaving groups they are) F is the most electronegative of them but is still the worst leaving group. Why? Because the carbon fluorine bond is so strong. The best leaving groups of the halides are bromide and iodide because the bigger size of the halogens means that the bond is longer and therefore weaker. OK that s all for today. Next time we will continue our discussion of neighboring group participation and also talk about carbocations.

Nucleophilic Substitution and Elimination

Nucleophilic Substitution and Elimination What does the term "nucleophilic substitution" imply? A nucleophile is an the electron rich species that will react with an electron poor species A substitution