P a g e | 1 The 22 Most Common Errors on Chemistry 232 Exams J. Wulff Department of Chemistry University of Victoria v. 0.1 July 2011 P a g e | 2 Introduction I taught 2nd year Organic Synthesis for the first time in the Spring of 2010, then taught the course again in 2011. Grading the exams for my second time through the course, I was struck by how many students made the same few errors again and again – particularly on the synthesis questions at the end of the exam. Often, the errors took different forms on different questions, such that students might not recognize that the error they were making on the final exam was the same as one that I had talked about in class, following the midterm. But perhaps 75% of the mistakes I saw on the last section of the exam could be grouped into about 20 different “big-picture” problems. This document is my attempt to spell out for you all of those problems. Think of it as a cheat sheet for my own exam. I’m telling you most of what you’re likely to get wrong, and I’m telling you ahead of time – while you can still do something about it. I’m not sure whether putting this on the course website will dramatically improve everyone’s performance on the final exam, or whether people will just find a way to invent new, ever more creative errors. Either way, I’ll hopefully have less of the same mistakes to correct in the future, which would be a win for me. My intention is for this document to evolve over the next few years (following my return to teaching 2nd year in 2013), to include more useful content and tips for final exams and midterms. You’ll notice from the cover page that it’s still in beta, and so you shouldn’t necessarily take what I say here as the final word on anything. Your textbook provides you with a lot more detail on most reactions than I do here, and my goal in these pages is not to replace either your coursenotes or your text. On the contrary, I’ve deliberately refrained from restating things that I’m explicit about in the lecture. The point of these notes is to provide you with a little bit of extra information so that you can avoid some particularly common errors that have tripped up students in past years. Once again: if you want to do well in the course, you still need to come to class every day, and you still need to read your textbook. I’ve focused on mistakes made in the synthesis questions because: (1) this section is worth the most points on my exams, and is possibly the most difficult; (2) the diversity of mistakes that people make is somewhat more limited than in the mechanism questions; (3) there’s a fair amount of “spillover” between the synthesis questions and other sections of the exam, such that what I tell you here might be useful in other parts too. One of the problems with talking about mistakes is that it requires me to write out incorrect reactions, by way of demonstration. I always worry when I do this, that students will somehow remember the wrong thing, but not necessarily remember that it’s wrong! To try to make sure this doesn’t happen, I’ve taken care to indicate incorrect reactions with an angry red X. The corrected forms of these reactions are designated by a cheerful blue check mark. Hopefully any reactions that stick in your head will do so along with the appropriate symbol. All of the incorrect responses that I’ve included are taken from answers to the Spring 2011 final exam (in some cases I’ve simplified the substrates for clarity). I hope you find this document useful. Please feel free to email me with your comments and suggestions, as I hope to add more content in the years to come. J. Wulff July 2011 P a g e | 3 Table of Contents Problem 1. Acid / Base Errors page 4 Problem 2. Random Functionalization of Alkanes page 6 + Problem 3. H3O Doesn’t do Everything page 7 Problem 4. Understanding the Difference Between H+ and H– page 7 Problem 5. Chemoselective Brominations page 9 Problem 6. Competing Ester Hydrolysis or Transesterification Reactions page 10 Problem 7. Amines are Nucleophiles – Even When You Don’t Want Them to Be! page 11 Problem 8. Friedel-Crafts Alkylations are Risky page 12 Problem 9. Crazy Reagents page 14 9a. Bifunctional methylenes page 14 9b. Made up electrophiles for Friedel-Crafts chemistry page 14 9c. Protecting groups that aren’t page 15 9d. Self-reacting species page 15 9e. Other reagents that are just too crazy for use page 16 Problem 10. It’s a carbon, not just a stick! page 17 Problem 11. Deoxygenations page 17 Problem 12. Carrying reactive species through multiple steps page 18 Problem 13. Keto-enol equilibria page 19 Problem 14. Friedel-Crafts reactions on saturated systems page 19 Problem 15. Cations on sp2 carbons page 19 Problem 16. Fischer esterifications page 21 Problem 17. The double-addition trap page 21 Problem 18. Mysterious oxidations page 22 Problem 19. Mysterious reductions page 23 Problem 20. Order of reactivities page 23 Problem 21. Poor choice of nucleophile / base page 24 Problem 22. Wishful thinking page 24 P a g e | 4 Problem 1. Acid / Base Errors The most common mistakes on synthesis questions are variations of the acid/base problem, where people want to use a strong base (or a strong nucleophile, which is ultimately the same thing) in the presence of an acidic proton. Some examples are shown below. 1.1 1.2 1.3 1.4 None of these reactions will work, because in each case we have a strong base in the presence of an acidic functional group. Let’s consider these reactions further. Reaction 1.1: In this reaction, we clearly intend for LDA to remove a proton next to the carbonyl (pKa ~ 25). But the carboxylic acid (pKa ~ 4.5) is much more acidic! So LDA will only end up deprotonating the acid to make a salt, and no desired product will be observed. How can we fix it? An ester is a synthetic equivalent for a carboxylic acid, because the ester can be hydrolyzed (e.g. KOH, MeOH) to afford the desired acid product. Protons on the carbon next to the ester function still have a pKa of around 25, but the ester itself does not contain any acidic protons. P a g e | 5 Reaction 1.2: In this reaction, the problem is not with the substrate (cyclopentenone) but with the electrophile that’s being added to it. This molecule contains an alcohol (pKa ~ 16) which is sufficiently acidic to react with the enolate of cyclopentanone (pKa ~ 20). How can we fix it? Putting a protecting group on the alcohol is the easiest way to solve the problem. Reaction 1.3: Here we’re generating a strong base (a Grignard reagent) in the presence of an acidic functional group (a phenol; pKa ~ 10). A proton transfer will happen very quickly to quench the Grignard. How can we fix it? Once again, a protecting group on the alcohol would solve the problem. Reaction 1.4: In this case, we’re trying to react a Wittig reagent with a ketone. Unfortunately, the ketone substrate also contains a carboxylic acid function (pKa ~ 4.5). Remember that the Wittig reagent is just a fancy carbanion, and is therefore quite basic (we generate it with nBuLi, after all!). This means that Wittig reagents will react with acids, alcohols, or phenols. How can we fix it? Using an ester in place of the carboxylic acid (as for reaction 1.1) would solve the problem. P a g e | 6 Problem 2. Random Functionalization of Alkanes I suspect this is more about wishful thinking on exams than it is about legitimate problems of understanding, but the sorts of reactions shown below (taken from the 2011 exam responses) are nonsense. 2.1 2.2 So what will happen in these reactions? The mechanisms for these two reactions are different, but both will ultimately give a reaction at the benzylic position. Oxidation (SeO2 or KMnO4) will lead to the installation of an alcohol, ketone or (under more forcing conditions) carboxylic acid at that position, while radical bromination will result in the installation of a bromine at the same spot on the molecule. In fact, functionalization of an alkane – in the absence of any other nearby functionality to help control the reaction – is an enormously difficult problem that’s an area of current interest in the synthetic literature (google: C-H activation). This brings up the idea of using synthetic handles to control your chemistry. If you want a carboxylic acid at the end of your alkyl chain, you really need to have something there first, that you can turn into a carboxylic acid at the appropriate time (e.g. an ester, or a primary alcohol). Alternatively, you could have some other functionality present at the next carbon over, which might allow you to brominate controllably at the desired position. P a g e | 7 + Problem 3. H3O Doesn’t do Everything There are a lot of reactions that we see in class (ester formation and hydrolysis, many types of deprotection reactions, eliminations, etc.) that are catalyzed by acid. And so – while I don’t exactly + condone the practice – I do sort of understand why people write “H3O ” when they can’t think of the right reagent to use for a reaction.