Chemistry 125: Lecture 17 October 12, 2009 Carbonyl, Amide, Carboxylic Acid, and Alkyl Lithium The first “half” of the semester ends by analyzing four functional groups in terms of the interaction of localized atomic or pairwise orbitals. Analyzing *C=O predicts a trajectory for attack by a high HOMO. Bürgi and Dunitz compared numerous crystal structures determined by X-ray diffraction in order to validate this prediction. 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. For copyright notice see final page of this file (to be supplemented with after-class Spartan session)

Shape of "Frontier" Orbitals LUMO Shape of "Frontier" Orbitals Plum Pudding MOs 3dxz (6 valence pairs) H C O 2s 2px 2py 2pz 3s 3dxy HOMO ABN Low LUMO AON 45% 2pO : 55% 2pC Pairwise Mixing Analysis Poor overlap () ; Poor E-match (2pO < 2pC)

0.03 0.1 0.3 0.01 0.003 e/ao3 C-O  Bonding 55% 2pO : 45% 2pC ? (1.5Å) (1.7Å) van der Waals radii O holds its electrons more closely than C Nodes through nuclei (AON), not between atoms (ABN) mostly a p-rich hybrid atomic orbital of Oxygen Lower of Oxygen’s “Unshared" Pairs some O-C bonding with backside of C hybrid some C-H bonding

until 1980s From what direction should a nucleophile HOMO approach the p* LUMO of the C=O group? H2C O Nu is better than (where Nu means “nucleophile”) Also Bürgi-Dunitz Angle

From what direction should a nucleophile HOMO approach furthest from nodes From what direction should a nucleophile HOMO approach the p* LUMO of the C=O group? Bürgi-Dunitz Angle

Bürgi-Dunitz Angle (110°) Structure Superposition from 14 Crystals (A-O) Containing N: and C=O N R C O from H. B. Bürgi, J. D. Dunitz Accts. Chem. Res. 16, 153 (1983) Bürgi-Dunitz Angle (110°) N.B. There is another R group directly behind this one.

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 mixing 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. BH2 H H2B LUMO+1 () 3-Center 2-Electron Bonds use only 2 AOs of each Li LUMO () Dimerization Vacant Li+ AOs stabilize unshared pairs of CH3 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 CH3OCH3 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 to form CH3Li • 3 O(CH3)2 Last Valence AO of each 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 (CH3)2O O(CH3)2 CH3OCH3 HOMO (1 of 4) Aggregation of (CH3Li)4 • 4 CH3OCH3

Spartan Demonstration you choose the functional group

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 1500 1800 1900 2000 1700 1600 Science & Force Laws Hooke Luther Reformation Bacon Instauration Columbus Navigation 1500 Copernicus Revolution Newton Gravitation 1800 Lavoisier Oxidation 1900 Planck Quantization 2000 Us 1700 1600 Science & Force Laws Hooke Coulomb Electron Bonds: Observation & Quantum Mechanics Schrödinger The Organic Structural Model & Chemistry

End of Lecture 17 Oct. 12, 2009 Continue for Optional Spartan Demo 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

Enol by Spartan The narrative for this timed ppt comes after the normal lecture on the same WMA file, following some after class questions. It begins at 57’36”. Click the forward arrow at 58’10”, after JMM says “So we want an enol. So we want to build a mol… we want to select that set of nuclei.” Sometimes the timing malfunctions a bit, which you can get around by pressing the arrow keys, if you wish.

0.003 0.03 0.3

End