1. Chemistry 125: Lecture 32 November 20, 2009 Resolution, Chiral Catalysis, and Conformational Energy Discussion of configuration concludes using esomeprazole as an example of three general methods for producing single enantiomers. A modification of Sharpless chiral catalyst for allylic epoxidation is used to prepare esomeprazole commercially. Conformational isomerism is more subtle than configurational because isomers differ only by rotation about single bonds, which requires careful physico-chemical consideration of energies and their relation to equilibrium and rate constants. Conformations have their own notation and nomenclature. Curiously, the barrier to rotation about the C-C bond of ethane was established by measuring its heat capacity. For copyright notice see final page of this file

2. Resolution of Omeprazole 1) Chromatography on SiO 2 coated with trisphenylcarbamoylcellulose (1990) Six Chromatograpy Injections  3 mg (+), 4 mg (-) Enough to Measure Racemization t 1/2 : 1 hr at 75°C, ~100 hr at 37°C Not enough for Human Dose (~20 mg) n R R R R R Ph-N C=O H R = R

3. H 2 C=O Resolution of Omeprazole 2) Reversible formation of crystalline mandelate ester (1994) Hundreds of mg - enough for biological testing. (R) four times as active as (S) in rats. Reversed in humans! (S)-mandelic acid separate diastereomers by crystallization H H C

4. Resolution a) Pasteur Conglomerate b) Temporary Diastereomers Destroy One Enantiomer React Racemate with Resolved Chiral Reagent or Catalyst Prepare only one Enantiomer a) Use resolved starting material b) Use resolved reagent/catalyst Generally lose half of the material (but see Levene’s 1,3-butandiol)

5. OR O OEt O O CO 2 Et RO Ti O 3) Chiral Catalysis by Titanium/Diethyltartrate R + RO Ligand Exchange Double Exchange with Diethyltartrate makes catalyst chiral

6. CH 2 C H O H C C H OH CH 2 H OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyltartrate R ROO RO + Ti O O O R OEt O CO 2 Et O RO Ti O O O OEt O CO 2 Et ** R CH 2 H C C C H H allyl alcohol (R)-“epoxide”  (S)-epoxide precursor Chiral “Oxidizing Agent” LUMO? HOMO? is diastereomeric! ( also p O +  * C=C )

7. Tsutomu Katsuki’s discovery -- a memorable day in 1980 at Stanford University! K. B Sharpless, with permission General ! i.e. 95:5

8. K. B Sharpless, with permission 5% L-Tartaric Acid

9. K. B Sharpless, with permission

11. 1980

12. RO ~ racemic OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyltartrate Ti (etc) ROO RO + Ti O O O Ti (etc) OEt O CO 2 Et O RO Ti O O O Ti (etc) OEt O CO 2 Et 94% e.e. (3% R) with added iPr 2 NEt (discovered in 2000) n ** R S R' O Ti O O O Ti (etc) OEt O CO 2 Et + (for no obvious reason) catalytic cycle RO ROO S R R' Chiral “Oxidizing Agent” R S R' + O R S O R S

13. ~ racemic OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyltartrate Ti (etc) ROO RO + Ti O O O Ti (etc) OEt O CO 2 Et O RO: Ti O O O Ti (etc) OEt O CO 2 Et R O 94% e.e. (3% R) add iPr 2 NEt AstraZeneca (2000) n ** R S R' O Ti O O O Ti (etc) OEt O CO 2 Et + (for no obvious reason) catalytic cycle RO ROO S R R' Chiral “Oxidizing Agent” R S R' O R S O R S add H 2 O! Kagan, Pitchen (1983) + R O RO Still

14. DFT calc. by Szab ó, et al. (2009) N(CH 3 ) 3 CH 3 -O-O Ti R-S-CH 3 CRUNCH! Something New in the Molecular Model!

15. One "C" to Go Composition Constitution "Stereoisomers" distinction based on bonding model Change by breaking bonds (van't Hoff) Change by rotating about single bonds (Paternó) Isomers Configuration Conformation HARD EASY Conformation

16. 19 th Century Organic Stereochemistry was Qualitative.

17. Conformation involving rotational isomerism about single bonds is more subtle, requiring quantitative thought about equilibria, rates, & energies.

18. GenealogyBottom Physical-Organic Chemistry

19. Genealogy Top Physical-Organic Chemistry

20. In the late 19th Century organic chemists focused their efforts on molecular structure, while physical chemists focused on energy. (sometimes to the exclusion of structure)

21. Principles of Chemistry An Introduction to all Chemical Textbooks by Wilhelm Ostwald 1907

22. In all 554 pages Ostwald used the word “atom” only this once - in the subordinate clause of a footnote! Footnote, p. 421 “Dalton, who developed the law of combining weights on the basis of an hypothesis he had pro- posed about the composition of matter from atoms, at first took hydrogen as unity, since it had the smallest ‘atomic weight’, i.e. combining weight.”

23. Dedication of Sterling Chemistry Laboratory April, 1923 G. N. Lewis (Student of Richards) T. W. Richards Wilder Bancroft Students of Ostwald

24. “ Ostwald's gift for leadership showed itself in the way his pupils regarded him all through their lives. Ostwald obituary by Wilder Bancroft (1933) They usually believed what Ostwald said even when they knew that he was not right.”

25. High St. Gibbs Ostwald became fixated on energy because he was so impressed by the man who lived here.

26. Josiah Willard Gibbs (1839-1904) ~1855

27. Physical Chemists were (and are) Quantitative about Equilibrium Constant (K) Rate Constant (k) Energy (E, or H, or G )

28. Energy determines what can happen (equilibrium) K = e -  E/kT and how fast (kinetics)  10 -(3/4)  E kcal/mole @ room Temp k (/sec) = 10 13 e -  E /kT ‡ ‡  10 13-(3/4)  E kcal/mole @ room Temp “activation” energy

29. Conformation involves rotational isomerism about single bonds.

30. How Free is Single-Bond Rotation? Paternó (1869) Not at all van't Hoff (1874) Entirely (Note that all are shown eclipsed) (Count Isomers)(Don’t Count Isomers) as are both versions of the ACS “molecule of the week” L-(+)-Tartaric Acid

31. Eclipsed The Newman Projection (1952) Melvin Newman 1908-1993 Yale '29, Ph.D. '32 Staggered Anti Syn (or fully eclipsed) Gauche (+) (-) (+) (-) conventional (but rare) by permission J. D. Roberts

32. IUPAC "Basic Terminology of Stereochemistry" Pure Appl. Chem. 68, 2193-2222 (1996) pretty pedantic

33. Is 3-Fold Barrier to Rotation Significant? 0°120° 240° 360° Torsional Angle Energy Is Energy Quantized in Triple Minimum?

34. Absorption of Heat by Ethane (1936) cal / mole / degree Depends on how much Heat is absorbed, For T = 298.1 K Barrier (kcal/mole) S Calculated 0.0 56.4 0.3 56.3 3.1 54.6 S Experimental 54.8  0.2 0 T CPCP T d T S "entropy" and on the Temperature at which it is absorbed. With larger quantized spacings, less Heat is absorbed, and at higher T,  smaller S.

35. 1Kcal Harmonic Oscillator at RT 81.9% 2.7% 14.8% 0.5%0.1% average  Equilibrium ratio of 0:1 quantum (or 1:2, etc.)?  10 3/4 = 5.6

36. 1Kcal Harmonic Oscillator at RT 364 cal/mol  1.2 cal/mol K @ 300 K (of 1.8) average  at 1 kcal 0.8% 4.2% lowest level 33% 59% 6% 2.7% 14.8% 81.9%

37. Is the Minimum eclipsed or staggered? 0°120° 240° 360° Torsional Angle Energy 3 kcal/mol

38. End of Lecture 32 Nov. 20, 2009 Copyright © J. M. McBride 2009. 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