1. Chemistry 125: Lecture 18 Amide, Carboxylic Acid, and Alkyl Lithium The first half of the semester ends by analyzing three functional groups in terms of the interaction of localized atomic or pairwise orbitals. Key properties of biological polypeptides derive from the mixing of localized orbitals that we associate with “resonance” of the amide group. The acidity of carboxylic acids and the aggregation of methyl lithium into solvated tetramers can be understood in analogous terms. More amazing than the power of modern experimental and theoretical tools is that their results did not surprise traditional organic chemists, who already had developed an understanding of organic structure with much cruder tools. The next quarter of the semester is aimed at understanding how our scientific predecessors developed the structural model and nomenclature of organic chemistry that we still use. Synchronize when the speaker finishes saying “…our theoretical study of bonds and reactivity.” Synchrony can be adjusted by using the pause(||) and run(>) controls. For copyright notice see final page of this file

2. Four Functional Groups: Carbonyl Amide Carboxylic Acid Alkyl Lithium (then we’ll have a complete change of perspective) 

3. Resonance: Intramolecular HOMO/LUMO Mixing Why the Amide Functional Group is not an Amine and a Ketone C N O

4. vs. Amide Pyramidal NPlanar N Easy N-C RotationBarrier to Rotation Amine Carbonyl StableMore Stable Naïve PredictionExperimental Observation by 16 kcal/mole (1/4 C-N) 16 kcal/mole by 0.14Å by 0.03Å wrecks  * C=O -n N overlap HOMO LUMO Long N-CShorter N-C … Short C=OLonger C=O … net (mostly) Opposing Dipoles Strongly Dipolar (in  direction) ~1/3 e - transfer N  O Crucial for Structural Biology O C  * C=O “LUMO” n N “HOMO” NN N might as well rehybridize Partial C=N Double Bond Partial C-O Single Bond n NH 3  * C=O Basic and AcidicRelatively Unreactive Skin works Resonance as a Make & Break correction to a naïve, localized initial drawing ! (best overlap)

5. formamide HOMO :  electron pair “from” N shared with C=O creates electric dipole

6. -- ++ Repeating Unit in Protein  -Helix Stabilized by electrostatic “Hydrogen Bonding” (reducing backbone “floppiness” by 1/3) and by local planarity of C-N - C-C groups O =

7. Acidity of Carboxylic Acids R-OH 10 11  stronger! R-C O OH pK a ~5 + H + R-C O O pK a ~16 R-O + H + HOMO/LUMO REALLY stabilizes carboxylate anion. R-C O O HOMO/LUMO stabilizes neutral acid compared to ROH. Predicts more uphill? R-C O OH + higher (Less “Uphill”)

8. LUMO+1 (  ) Aggregation of CH 3 Li HOMO (  ) LUMO (  )

9. Aggregation of CH 3 Li HOMO (  ) LUMO+1 (  ) 2HOMO (  ) 2LUMO+1 (  ) Dimerization

10. Aggregation of CH 3 Li 3-Center 2-Electron Bonds use 2 AOs of each Li LUMO (  ) LUMO+1 (  ) Dimerization Rotate to superimpose the red lobes. Two vacant Li + AOs stabilize unshared pair of C

11. Aggregation of CH 3 Li HOMO (  ) LUMO+1 (  ) rotated 90° LUMO+1 (  ) HOMO (  )

12. Aggregation of (CH 3 Li) 4 HOMO (1 of 4) LUMO (1 of 4) Distorted Cubic Tetramer 4-Center 2-Electron Bond H3CH3CCH 3 O : Excess Ether Rips Aggregates Apart by bonding with Li AOs. 4 CH 3 OCH 3 NON-BONDED INTERACTIONS & SOLVENT EFFECTS ARE A VITAL PART OF LORE. (e.g. facilitating ionization) Last Valence AO of Li (vacant) 3 vacant Li + AOs stabilize unshared pair of C.

13. But organic chemists were not at all surprised by what they showed! We have seen amazing modern tools for revealing the Å / psec world of molecules: SPM X-ray Diffraction Spectroscopy: IR, ESR, (NMR, etc.) Quantum Mechanics (computer "experiments")

14. How Did They Know?

15. 17th Century 1800 Lavoisier Oxidation 1900 Planck Quantization Newton Gravitation Bacon Instauration Luther Reformation Columbus Navigation 2000 Us 17001600 Robt. Hooke (1635-1703) 1500 Copernicus Revolution Hooke (1665) Science & Force Laws Electron bonds: observation & quantum mechanics Development of the Organic Structural Model

16. Yale Chemistry 1901S Greek symbols denote substituent positions.  Cf. Clairvoyant Benzene

17. Sheffield Chemistry Lab (SSS) (only quantitative tool)

18. Yale Chemistry 1901S Balance Burettes Analytical Balances Were Not Portable Quantitative Tools? C. Mahlon Kline (1901S)

19. Kline Chemistry Laboratory (1964) Kline Biology Tower (1965)

20. Quartz

21. Silliman Crystal

23. Boyle Lavoisier

24. Berzelius etc.

25. Wöhler/Liebig

26. Genealogy

27. GenealogyBottom

28. Genealogy Top

29. End of Lecture 18 Oct. 15, 2008 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