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

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

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

*C=O nNH3 Carbonyl vs. Amide Amine Resonance as a HOMO LUMO net Naïve Prediction Experimental Observation Resonance as a Make & Break correction to a naïve, localized initial drawing Stable More Stable by 16 kcal/mole (1/4 C-N) Long N-C Shorter N-C … by 0.14Å Crucial for Structural Biology Short C=O Longer C=O … by 0.03Å O C *C=O “LUMO” Pyramidal N Planar N ! (best overlap) N N N Easy N-C Rotation Barrier to Rotation 16 kcal/mole wrecks *C=O-nN overlap Basic and Acidic nN “HOMO” nNH3 *C=O Relatively Unreactive Skin works might as well rehybridize (mostly) Opposing Dipoles Partial C=N Double Bond Strongly Dipolar (in  direction) Partial C-O Single Bond ~1/3 e- transfer N  O

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

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

Acidity of Carboxylic Acids R-OH pKa ~16 R-O + H+ R-C O OH pKa ~5 + H+ R-C O HOMO/LUMO stabilizes neutral acid compared to ROH. Predicts more uphill? R-C O OH + HOMO/LUMO REALLY stabilizes carboxylate anion. R-C O 1011  stronger! (Less “Uphill”) higher

LUMO () LUMO+1 () HOMO () Aggregation of CH3Li

Aggregation of CH3Li LUMO+1 () 2HOMO () Dimerization 2LUMO+1 ()

Rotate to superimpose the red lobes. LUMO+1 () 3-Center 2-Electron Bonds use 2 AOs of each Li LUMO () Dimerization Two vacant Li+ AOs stabilize unshared pair of C Aggregation of CH3Li

Aggregation of CH3Li LUMO+1 () HOMO () HOMO () LUMO+1 () rotated 90° Aggregation of CH3Li

Aggregation of (CH3Li)4 • 4 CH3OCH3 H3C CH3 O : LUMO HOMO NON-BONDED INTERACTIONS & SOLVENT EFFECTS ARE A VITAL PART OF LORE. (e.g. facilitating ionization) Excess Ether Rips Aggregates Apart by bonding with Li AOs. Last Valence AO of Li (vacant) H3C CH3 O : LUMO (1 of 4) 3 vacant Li+ AOs stabilize unshared pair of C. Distorted Cubic Tetramer 4-Center 2-Electron Bond HOMO (1 of 4) Aggregation of (CH3Li)4 • 4 CH3OCH3

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") But organic chemists were not at all surprised by what they showed!

How Did They Know?

17th Century 1800 Lavoisier Oxidation 1900 Planck Quantization Newton Gravitation Bacon Instauration Luther Reformation Columbus Navigation 2000 Us 1700 1600 Robt. Hooke (1635-1703) 1500 Copernicus Revolution Hooke (1665) Science & Force Laws Development of the Organic Structural Model Electron bonds: observation & quantum mechanics

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

Sheffield Chemistry Lab (SSS) (only quantitative tool)

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

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

Quartz

Silliman Crystal

Silliman Crystal

Boyle Lavoisier

Berzelius etc.

Wöhler/Liebig

Genealogy

GenealogyBottom

Genealogy Top

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). 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