Chemistry 125: Lecture 18 October 11, 2010 Amide, Carboxylic Acid, and Alkyl Lithium; Background of the Chemical Revolution (Beginning to 1789) For copyright notice see final page of this file 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. Studying the logic of the development of modern theory, technique and nomenclature helps to use them more effectively. Chronological treatments of organic chemistry often begin with Lavoisier, the father of modern chemistry. But his “Chemical Revolution” depended upon the practices of ancient technology and alchemy and discoveries like those of Scheele, the Swedish apothecary who discovered oxygen and prepared the first pure samples of organic acids

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

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 HOMO LUMO Long N-CShorter N-C … Short C=OLonger C=O … (mostly) Opposing Dipoles net Strongly Dipolar (in  direction) ~1/3 e - transfer N  O Crucial for Structural Biology Basic and AcidicRelatively Unreactive Skin works ! (best overlap)

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

-- ++ 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 = -- ++ ++

Four Functional Groups: Carbonyl Amide Carboxylic Acid Alkyl Lithium  

Acidity of Carboxylic Acids R-OH  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 mixing stabilizes neutral acid compared to ROH. R-C O OH + higher (Less “Uphill”) Predicts more uphill?

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

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

Aggregation of CH 3 Li 3-Center 2-Electron Bonds use only 2 of the 4 valence AOs of each Li LUMO (  ) in Li-C-Li-C plane LUMO+1 (  ) out of plane Dimerization Rotate to superimpose the red lobes. BH 2 H H H2BH2B Vacant Li + AOs stabilize unshared pairs of CH 3

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

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 : 4 CH 3 OCH 3 Last Valence AO of each Li (vacant) 3 vacant Li + AOs stabilize unshared pair of C. (CH 3 ) 2 OO(CH 3 ) 2 CH 3 OCH 3 This is as baroque as we will get in this course.

Aggregation of (CH 3 Li) 4 Excess Ether Rips Aggregates Apart by bonding with Li-AOs to form CH 3 Li 3 O(CH 3 ) 2 4 CH 3 OCH 3 HOMO “NON-BONDED” INTERACTIONS & SOLVENT EFFECTS ARE A VITAL PART OF LORE. (e.g. facilitating ionization)

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")

How Did They Know?

17th Century 1800 Lavoisier Oxidation 1900 Planck Quantization Newton Gravitation Bacon Instauration Luther Reformation Columbus Navigation 2000 Us Copernicus Revolution Hooke (1665) The Organic Structural Model & Chemistry Science & Force Laws HookeCoulomb Electron Bonds: Observation & Quantum Mechanics Schrödinger

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

Sheffield Chemistry Lab (SSS) (only quantitative tool)

Yale Chemistry 1901S Balance Burettes The precious Analytical Balances were key, but were not portable Quantitative Tools? C. Mahlon Kline (1901S)

Kline Chemistry Laboratory (1964) Kline Biology Tower (1965) #4 in Big Pharma (2010)

Quartz Crystals for Purity and Quantitation (face angles)

Silliman Crystal

Boyle Lavoisier

Berzelius etc.

Wöhler/Liebig

Genealogy

GenealogyBottom YOU resonance, x-ray, proteins

Genealogy Top

Background in Ancient Arts and Lore Noah Mosaic 12 th Century ) Sicily (Monreale) “Florence” Flask

Roman Glass Perfume Vial ~2000 years old Class of 1954 Chemical Research Building -5 days old

All the philosophy of nature which is now received, is either the philosophy of the Grecians, or that other of the alchemists… The one is gathered out of a few vulgar observations, and the other out of a few experiments of a furnace. The one never faileth to multiply words, and the other ever faileth to multiply gold. Francis Bacon ( )

Bega Alchemist 1663 e.g. Newton OCCULT Title of Exhibition on Alchemy at the Beinecke Library 2009 “The Book of Secrets”

Mellon ms 41 Elements ~1570 Beinecke Library, Yale Visio mystica Arnold of Villanova 13 th Century (England ~1570)

On the Philosopher’s Stone (13 th Cent; Basel, 1571) Beinecke Library, Yale

alchemist Paracelsus (early 1500s) Poison Ivy Doctrine of Sympathies In nature antidotes are to be found near the source of illness. ©2006 Derek Ramsey Jewel Weed Double-blind Clinical Test (1997) No better than water OH

Salicilic Acid Willow (Salix) found in malarial swamps Salicin (from bark) hydrolyze oxidize

“Vade mecum” Alchemical Lab Manual Caspar Harttung vom Hoff (Austria, 1557) Beinecke Library, Yale

Carl Wilhelm Scheele ( ) Prerevolutionary Pharmacist Carl Wilhelm Scheele ( )

End of Lecture 18 Oct. 11, 2010 Copyright © J. M. McBride 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