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Chemistry 125: Lecture 32 Stereotopicity and Baeyer Strain Theory

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1 Chemistry 125: Lecture 32 Stereotopicity and Baeyer Strain Theory
Why ethane has a rotational barrier is still debatable. Analyzing conformational and configurational stereotopicity relationships among constitutionally equivalent groups reveals a subtle discrimination in enzyme reactions. When Baeyer suggested strain-induced reactivity due to distorting bond angles away from those in an ideal tetrahedron, he assumed that the cyclohexane ring is flat. He was soon corrected by clever young Hermann Sachse, but Sachse’s weakness in rhetoric led to a quarter-century of confusion. Synchronize when the speaker finishes saying “…and that you could measure the barrier.” Synchrony can be adjusted by using the pause(||) and run(>) controls. For copyright notice see final page of this file

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

3 (various approximations)
Latest Word Experiment cm-1 x 2.86 = cal/mole Quantum Theory (various approximations) ~2.7 kcal/mole ~2.9 kcal/mole

4 What is the source of the ~3 kcal/mole barrier in Ethane?
(a) Eclipsed form destabilized or (b) Staggered form stabilized? C H C H (Compared to what?) H-H repulsion only 3.4 kcal/mole for propane (so "size" of H is not very important) e-e repulsion But there are also p-e attractions.

5 What is the source of the ~3 kcal/mole barrier in Ethane?
(a) Eclipsed form destabilized or (b) Staggered form stabilized? C H + _ HOMO/LUMO mixing C=C H+ H _ "hyperconjugation" s s

6 A Digression on Topicity (Placeness)
Are these two protons equivalent? and their properties Yes, but their environments are different. D + H C O : + + H H pKa ~16 Exchanges readily with acidic water Doesn’t exchange pKa ~50 These protons are “heterotopic” (Greek: ó, topos = place) Protons within the blue (or green) set are “homotopic” Here we are discussing constitution; the distinctions are less trivial and more useful when they are stereochemical.

7 Stereotopic Relationships
among atoms (or groups) that are constitutionally homotopic enantiotopic H C O H diastereotopic enantiotopic These distinctions are only conformational. They are erased by rotation within ~10-12 sec. This distinction is configurational and lasts as long as bonds endure.

8 Toponymy OH H pro-S pro-R O H C H
among atoms (or groups) that are constitutionally homotopic H C O H “prochiral” C (i.e. would be chiral, if the enantiotopic atoms differed) 2 1 H OH enantiotopic Give higher priority to enantiotopic H being named. 3 4 4 3 pro-S pro-R

9 Reactivity Difference?
among atoms (or groups) that are constitutionally homotopic Attacks by a reagent like Cl• are mirror images and thus identical in rate. H OH Cl• •Cl pro-S pro-R

10 Reactivity Difference?
among atoms (or groups) that are constitutionally homotopic Attacks by a resolved chiral reagent are diastereomeric and should have different rates. H OH Right Right pro-S pro-R

11 Establishing Enzyme Specificity
O-H D H O D LAD + NADH + NAD+ If horse liver alcohol dehydrogenase (LAD) removes only the pro-R H from ethanol, it should remove H (never D) from (S)-1-deuteroethanol. Westheimer [J. Am. Chem. Soc., 1951, 73, 2043; J. Biol. Chem., 1953, 202, 687] “Stereospecificity in Enzymology: Its Place in Evolution”,Topics in Stereochemistry, Volume 19 , Pages , 1989. Steven A. Benner (Chem 125 alumnus), Arthur Glasfeld, Joseph A. Piccirilli These focus more on selectivity between the enantiotopic hydrogens of the cofactor NAD(P)H than on those of the substrate. Good test, but where to get the (S)-1-deuteroethanol? By starting with same catalyst, CH3CDO and excess NADH. A full cycle returns CH3CDO with all of its initial D intact! [This proves specificity. Whether pro-R or pro-S required more work.] Actually LAD is a catalyst for oxidation by “NAD+”.

12 Baeyer Strain Theory (1885)
Adolf von Baeyer Academy of Science, Munich, 1893 See

13 On Polyacetylene Compounds (1885)
They explode! (Dr. Homolka?) 1. Theory of Ring Closure and the Double Bond Ring closure is apparently the only phenomenon that can supply information about the arrangement of atoms in space. Since a chain of 5 or 6 members can be closed easily, while with one of more or fewer members it is difficult or impossible, spatial factors are apparently involved.

14 The previously proposed general rules on the nature of carbon atoms are the following:
I. Carbon is as a rule tetravalent. II. The four valences are equivalent, as shown by the fact that there is only one monosubstitution product of methane. III. The four valences are equivalently arranged in space and corres-pond to the corners of a regular tetrahedron inscribed in a sphere. IV. The atoms or groups attached to the four valences cannot exchange places. Evidence: there are two tetrasubstitution products abcd of methane, LeBel-van't Hoff Rule. V. Carbon atoms can bind to one another with 1, 2, or 3 valences. VI. These compounds can form either open or closed-ring chains.

15 I should like to add the following to these generally accepted rules:
VII. The four valences of the carbon atom point in the directions connecting the center of the sphere to the corners of the tetrahedron, forming an angle of 109°28' with one another. The direction of attachment can undergo alteration, but a strain is generated increasing with the size of the deflection

16 Dimethylene is indeed the weakest ring, which can be opened by hydrogen bromide, bromine and even iodine; trimethylene is broken only by hydrogen bromide but not by bromine; finally tetramethylene and hexamethylene are difficult or impossible to break.

17 Sachse (1890)

18 Sachse (1890)

19 "It is not possible to write an abstract of this paper, especially since the author's explanations are hardly understandable without models." Julius Wagner (1890)

20 Baeyer (1890) A further proposal is that the atoms in hexamethylene are arranged as in Kekulé's model, that is that the arrangement of the atoms in space is the one with a minimum distortion of the valence directions. Thus the 6 carbon atoms must lie in one plane and 6 hydrogen atoms lie in each of two equidistant parallel planes. Further each of the 12 hydrogen atoms must have the same position relative to the other 17 atoms. The experimental test of the correctness of this assumption is relatively easy, for example sufficient evidence is that there is a single isomer of hexahydrobenzoic acid [i.e. only one cyclohexane carboxylic acid]. Meanwhile, as long as our knowledge in this field is so incomplete, we must be satisfied that the above assumption is the most likely, and no known fact contradicts it.

21 Sachse (1892) 41 pp. in Zeitschrift für Physikalische Chemie
edited by Ostwald, who did not believe in atoms and wrote dispar-agingly of his successor in Riga, "Scientifically he had been brought up in the narrow circle of contemporary organic chemistry, and to him the arrangement in space of the atoms of organic compounds was the foremost of all conceivable problems."

22 Sachse (1893) 34 pp. in Zeitschrift für Physikalische Chemie
died at age 31 in 1893 Baeyer (1905) "Sachse…disagreed with my opinion that larger rings are planar. He is certainly right from a mathematical point of view; yet in reality, strangely enough, my theory appears to be correct. The reason is not clear…"

23 What important lesson should we all take from the tale of poor Sachse?

24 Sachse (1890)

25 Bragg & Bragg (1913) Diamond Structure by X-ray
Ernst Mohr (1918)

26 End of Lecture 32 Nov. 21, 2008 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). 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

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