1. Chemistry 125: Lecture 47 February 2, 2011 S N 2, E2, S N 1, E1 an Instructive Project Alkenes: Stability and Addition Mechanisms This For copyright notice see final page of this file

2. CH 3 CCH 2 CH 3 + via S N 1 and E1 Demonstrates Cation Intermediate CH 3 CCH 2 I CH 3 CCH 2 CH 3 OH AgNO 3 H2OH2O Ag + CH 3 CCH 2 CH 3 + 1° Cation (unstable) + CH 3 CCH 2 CH 3 3° Cation (stable) -H +  C-C as nucleophile in “S N 2” (e.g. J&F sec. 7.6-7.8) “Skeletal” Rearrangement

3. Doubleor ? CC H CC H CC H MinimumSingle HOMO-1 LUMO HOMO LUMO+1 “Hyperconjugation” (  HOMO-LUMO mixing) CC H CC H CC H CC H

4. CCCCCC H 2 CH Doubleor ?MinimumSingle LUMO+1 HOMO H H H

5. CH 3 CCCCCC H 2 CH Doubleor ?MinimumSingle “ ” LUMO+1 HOMO-7

6. S N 1 and E1 Short-Lived Ion Pair Gives Cl OHHO 40% retention60% inversion acetone H 2 O Cl - + Cl - temporarily blocks the “retention” face. Net Inversion! H 2 O: 80% racemization (should be 100% if there is a planar intermediate cation) (e.g. J&F sec. 7.6-7.8)

7. EtOH/H 2 O (4:1) 55°C NaOH + tBu-BrHO-t-Bu + NaBr (0.01 M) + CH 2 =C(CH 3 ) 2 E2 or E1? How do you tell? Overall rate (not just % alkene) depends on [OH - ] Kinetic Isotope Effect shows whether H is being transferred in rate-determining step.

8. CH 3 -Br + OH - 5. (5 min) Give a real example of the influence of a change of reactant structure on the ratio of S N 2 to E2 products. Be as specific and quantitative as you can. (You will need to show the ratios for two different reactants.) (CH 3 ) 3 C-Br + OH - Perspectives on Drastic Ratios Synthetic Organic Chemist : Reliable High-Yield Tool Physical-Organic Chemist : Definitive E a Difference Unambiguous interpretation of cause e.g. 10 3 Steric retardation of i-Pr via S N 2 vs. 10 5 acceleration for t-Butyl via S N 1

9. Perspectives on 50:50 Product Ratios Physical-Organic Chemist : Valuable “Borderline” Reference Synthetic Organic Chemist : Deadly Influence on 12-Step Synthesis (1/2) 12 = 0.02% Yield (Might provide optimizable lead) Allows Sensitive Tests of Subtle Influences. e.g. isotope effect by competition

10. A valuable lesson from E2 Elimination

11. If Step 1 (motion) is rate-limiting, H- and D-transfer products should form in equal amounts. (because their motions should be equally fast) If Step 2 (atom shift) is rate-limiting, more H-transfer product should form. k H /k D > 1 (kinetic “isotope effect”) In a Very Viscous Solvent Can Short-Range Motion Constitute a Rate- (and Product-) Determining Step? Generates steric hindrance & requires moving radicals past N 2 N N CH 3 CH 3 H 3 C CD 3 CD 3 CD 3 UV Light CH 3 CH 3 H 3 C CD 3 CD 3 CD 3 Radical-Pair Combination CH 3 CH 3 H 3 C CD 2 CD 3 CD 3 D D (1) Rotate N 2 + C 4 D 9 (2) Shift D atom exothermic/easy/fast N N Radical-Pair “Disproportionation” (1) Rotate N 2 + C 4 H 9 (2) Shift H atom exothermic/easy/faster CD 3 CD 3 CD 3 CH 3 H 3 C CH 3 H CH 2 Jo-David’s Question: N N N N

12. t-Butylhydrazine ? To do his project, Jo-David needed to prepare this compound. E2 >> S N 2 CD 3 double arrow for “retrosynthesis” i.e. prepare from E1 >> S N 1

13. Smith-Lakritz

14. Ph 2 C=N-R  Ph 2 C=O + H 2 N-R + H + + It is very common to change a C=X double bond into C=O and H 2 X (we’ll be discussing this) But if

15. - + t-Butylhydrazine ??? Jo-David Fine April-October 1971 O CD 3

16. Jo David Fine Jo-David Fine Notebook p. 91 (October 1971)

17. Jo-David is now a respected professor of dermatology at Vanderbilt, and a world expert on Epidermolysis Bullosa. His son graduated from Yale in 2000. Happy Ending I: “…that project (and my conversation with that pleasant prof at U Michigan) did teach me more about the rigors and foibles of bench research than anything that I subsequently experienced as a postdoc at NIH. It therefore prepared me for many more happily transient foibles during the 19 years that I ran a bench immunology lab at UAB and UNC. As I found out the hard way, trying to predict ‘good behavior’ with cell lines, antibodies, and semi-purified proteins was even more subject to random whimsy than when I was trying to work with relatively straightforward purified chemicals in a far more structured laboratory setting as an undergrad. Jo-David Fine MD, MPH, FRCP (London) January 30, 2011

18. Crucial Lesson (from S. Nelsen, U. Wisc.) 95% 5% S N 1 When you need a compound, % yield isn’t everything! HCl salt easily purified by crystallization E1 / E2 Major product a gas, just “goes away” CD 3 Cheap!

19. Happy Ending II : Jo-David Fine’s successor found that in fluid solvents, there was more H- than D-transfer (atom transfer is rate-limiting), but that in very viscous solvents at low temperature this “kinetic isotope effect” disappeared (there were equal amounts of H- and D-transfer), because motion had indeed become rate-limiting.

20. Coverage to Here for the Exam on Friday 10:30-11:30 in SCL 160 or 10:15-11:15 in SCL 111 Review 8-10 pm this evening

21. El and Nu can be the same molecule! “Electrophilic” Addition to Alkenes This CC H L + Leaving GroupNucleophile High HOMO Low LUMO Electrophile El Nu Mechanistic/Synthetic Questions: Timing (Concerted or Stepwise) Stereochemistry (Syn or Anti) Regiochemistry or Orientation (“Markovnikov” CH 3 H H reverse of E1/E2 with some names changed or “Anti-Markovnikov”) H HOMO/LUMO or SOMO? X “For unto every one that hath shall be given, and he shall have abundance.” --------- Matthew 25:29 (Cf. contemporary economics) What can you make?

22. 28:17-31:58

23. Thermodynamic Stability of Butenes http://webbook.nist.gov/chemistry/

30. Use NIST Webbook to study factors influencing relative stability of butenes For high precision convert to a common product, butane, using catalytic hydrogenation, which is fast and clean, and much less exothermic than combustion.

31. Isomeric Hexenes  H f Problem: Are these data consistent with those for the butenes?

32. End of Lecture 47 February 2, 2011 Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0