CHM235 F22 Chapter 7 Handout(1)

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CHM235 F22 Chapter 7 Handout: Alkyl Halides Dr. Sandler Read chapter 7 and watch the accompanying video lectures. 1. Intro 1. What is an alkyl halide? And what is it about alkyl halides that makes them a nice place for us to start thinking about chemical reactivity? 2. a. What’s the deal with the “alpha position,” “beta position,” etc.? b. What about primary (1°), secondary (2°), and tertiary (3°)? 3. What are organohalides/alkyl halides good for? And what is not quite right about that kind of statement? 4. a. What is the difference between a substitution reaction and an elimination reaction? Specifically, Sn1, Sn2, E1, and E2? b. Draw curved-arrow mechanisms for an Sn2 reaction and for an E2 reaction, between 2-chloropropane and NaOH. Identify the nucleophile, electrophile, and leaving group in these reactions. (And what are nucleophiles and electrophiles, anyway?) c. Draw curved-arrow mechanisms for an Sn1 and an E1 reaction between tert-butyl chloride and H 2 O. Identify the nucleophile, electrophile, and leaving group in these reactions. Why didn’t an Sn2 or E2 reaction happen? And can you control whether Sn1 or E1 happens? And why didn’t an Sn1 or E1 reaction happen in the reaction from 4b? d. What reaction would you expect from tert-butyl chloride and NaOH? Why? e. Why were the nucleophiles good nucleophiles? And ditto for the electrophiles, and the leaving groups? Why does it make logical sense that a good leaving group is a weak base (i.e. the conjugate base of a strong acid?) f. Experimentally, how can you tell whether (for example) a substitution has an Sn2 mechanism or an Sn1 mechanism? g. Wait a minute- even in a “unimolecular” mechanism, there are two molecules involved, right? So why does the reaction have first-order kinetics? 2. Nucleophiles and bases 5. Let’s think back to question 4b. “Draw curved-arrow mechanisms for an Sn2 reaction and for an E2 reaction, between 2-chloropropane and NaOH.” How could you make sure an E2 reaction happened instead of an Sn2? a. What is the connection between nucleophilicity and basicity? Why? And why is it more complicated than that? b. Which is more nucleophilic: OH - or H 2 O? Why? And which is more basic? c. What about tert-butoxide? How does it compare? In this particular case, why are basicity and nucleophilicity not the same thing? And why is that a good thing ? Page 1 of 5

CHM235 F22 Chapter 7 Handout: Alkyl Halides Dr. Sandler d. Which is more nucleophilic: F - or I - ? Why? And which is more basic? What’s going on here? e. Classify the following as strong vs. weak bases, and strong vs. weak nucleophiles. (The structure of DBN is at right. What gives DBN its useful and distinctive properties re: basicity and nucleophilicity?) NaH DBN NaOEt EtOH HS - H 2 S 3. Sn2 reactions Sn2 Substitutions: 6. a. Let’s focus on Sn2 some more. What is the transition state of an Sn2 reaction like? And what does it mean for it to be a “concerted” reaction? b. Suppose HS - attacks (R)-2-bromobutane. What product will you get? What does “inversion of configuration” mean? c. Would you get inversion of configuration in an Sn1 reaction? 7. a. Suppose you want to react bromocyclohexane with NaF. Should you use water, benzene, or acetone as the solvent? Draw some diagrams showing interactions between Na + and F - , and between solvent molecules and F - , to find out. b. Define “nonpolar solvent,” “polar protic solvent,” and “polar aprotic solvent.” 8. Cells like to methylate things using S-adenosyl methionine (SAM.) a. Where is the electrophile on this molecule? And why is it so electrophilic? Draw a curved-arrow mechanism in which an amino group gets methylated by SAM. b. Is the S a chiral center? Why? And if so, is it R or S? (Hint: what is the atomic number of a lone pair?) 4. Alkenes 9. Since we’re going to be talking about eliminations, and eliminations form alkenes, let’s talk about how to name alkenes. Name the following: Page 2 of 5

CHM235 F22 Chapter 7 Handout: Alkyl Halides Dr. Sandler 10. a. How does cis vs trans isomerism affect the stability of alkenes? Why? b. What about the degree of substitution of the C=C double bond? Explain. 11. a. Draw some products of the reactions at left, and indicate which is the major product, and why. b. Define: regioselective, regiospecific, stereoselective, stereospecific. 5. Anti-periplanar elimination 12. Predict the products of the E2 eliminations at right. While you’re at it, draw Newman projections of the transition states. And is this stereoselective, or stereospecific? Page 3 of 5

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CHM235 F22 Chapter 7 Handout: Alkyl Halides Dr. Sandler 13. What do you get if cis -1-iodo-2-methyl-cyclohexane is treated with a strong base (but weak nucleophile) like DBN? And what about for the trans isomer? Since these are cyclohexanes, you should probably start by drawing each of them in both possible chair configurations. 6. Sn1 and E1 revisited 14. a. Suppose you dissolve tert -butyl bromide in ethanol and heat it. Give as many reasons as you can to explain why neither an Sn2 reaction nor an E2 reaction is going to happen. b. Draw mechanisms for the Sn1 and E1 reactions for those reagents. c. Wait a minute- if EtOH is such a weak base, how is it able to pull protons off the intermediates? d. What about this? Would you expect Sn1 or E1 to happen? What about Sn2? 15. a. In general, how can you control whether the E1 or Sn1 product is formed? What’s that? You can’t? Then why are we studying this? b. Here’s the reaction in which squalene epoxide is converted into lanosterol. What is the mechanism like? And how is it controlled? c. BTW, squalene epoxide is a pretty noodly molecule, while lanosterol is pretty rigid. What is the  S for this process? Or the  G? What’s going on? 7. Hydride and methyl shifts 16. a. What substitution products do you get when you heat 2-bromo-3-methyl butane in water? (NOTE: how do you know this will be an Sn1 instead of an Sn2 reaction?) b. How do you know which way the hydride group will shift? Why does it shift? c. What about the substitution products when you use 2-bromo-(3,3)-dimethyl butane? 8. Solvent effects 17. a. Rank the following, in terms of their suitability for Sn1 and E1 reactions: polar protic solvents, polar aprotic, and apolar. b. Draw reaction coordinate diagrams to show how solvent choice affects the rate of the reaction (specifically, protic vs. polar aprotic for Sn2 vs. Sn1.) Page 4 of 5

CHM235 F22 Chapter 7 Handout: Alkyl Halides Dr. Sandler 9. Putting it all together. 18. Let’s recap. What is the difference between Sn1, Sn2, E1, and E2? Under what circumstances does each happen? 19. Here are some reactions from pg. 342 of your textbook. Let’s go through them and predict the products. Remember: • First you want to ask whether the reagent is a good base or a good nucleophile, or both, or neither. Don’t forget to ask what effect the solvent might have. • Second , look at the starting material and ask what a nucleophile (or a base) would do to it. Is a carbocation likely to form? What effect might the solvent have? • Third, don’t forget to ask about regioselectivity and stereoselectivity issues. Zaitsev’s rule, inversion of configuration, anti-periplanar arrangements, etc. (NOTE: “b” has a tertiary alkyl halide. BUT, is it likely to make a carbocation under these conditions? Why or why not?) Page 5 of 5