Chemistry 125: Lecture 74 April 27, 2011 The Structure of Glucose and Synthesis of Two Un-Natural Products This For copyright notice see final page of this file

“ose” soonbecame the generic suffix for sugars Carbohydrate (C•HOH)n “I may be allowed to denote compounds [with] carbon plus hydrogen and oxygen in the same ratio that obtains in water…as carbohydrates” Schmidt (1844) CHOH Grape Sugar (1792) γλεῦκος gleukos “sweetness” Glucose Dumas (1838) H OH Couper 1858 “ose” soonbecame the generic suffix for sugars

Carbohydrate (C•HOH)n C=O CHOH H aldose CHOH C=O H ketose CHOH (e.g. glucose) CHOH C=O H ketose (e.g. fructose) CHOH

We know the structure of glucose by spectroscopy no aldehyde or ketone! http://riodb01.ibase.aist.go.jp/sdbs/

Crystalline Glucose upon dissolution in D2O 1H-NMR 13C-NMR Crystalline Glucose upon dissolution in D2O [a]D = 112° “dextrose” After 1 day in D2O no aldehyde or ketone no aldehyde [a]D = 53° J 7.9Hz 3.7Hz [a]D = 19° gauche anti H H hemiketal with H+ or OH- Cf. J. E. Gurst, J. Chem. Ed. 1003 (1991)

We know the structure of glucose by spectroscopy and X-ray Diffraction. But how could they know?

Chirality - van’t Hoff (1877) Fructose H+ (1876) Manna Mannose (1888) HNO3 Mannitol reduced oxidized Sucrose Galactose Arabinose Gum Arabic (1873)

Heinrich Kiliani 1855-1945

While a large number of compounds are very easily formed upon oxidation of dextrose by dilute nitric acid or by halogens, these molecules retain 6 carbon bound together in a chain. Under the same conditions laevulose yields substances containing chains with a smaller number of carbons (glycolic acid and inactive tartaric acid). Here oxidation causes immediate splitting of the molecule, a fact which means that laevulose is a ketone.1) Bearing in mind further the fact that laevulose in transformed into mannitol by nascent hydrogen 2), one comes to the conclusion that laevulose must be adjudged to have one of the following two constitutional formulae: Berlin 1885

One could hope to distinguish definitively between one and the other formula, by succeeding in adding hydrocyanic acid to the ketone radical of laevulose and transforming the cyanhydrin into the corresponding carboxylic acid. Since the carboxylic acid from compound I above KOH (STRONG) 1) HCN HCl (fuming) HI / P ? “does not agree with the description that Hecht gives of the Ca salt of methylbutyacetic acid,” Ca, Ba, Sr, Pb salts all agree must upon exhaustive reduction by concentrated hydriodic acid yield methylbutylacetic acid, and on the contrary the carboxylic acid from compound II under the same conditions leads to ethylpropylacetic acid. NOT from Laevulose! Kiliani 1886 “which means that my heptanoic acid is identical with [unknown] ethylpropylacetic acid.” ? KOH (STRONG) NOT ketone! RCO2- + CH3CO2-

Heinrich Kiliani: On the Composition and Constitution of Arabinosecarboxylic Acid and of Arabinose In a report dated 27 November 1886 I showed on one hand that arabaric acid formed by oxidation of arabinose has the formula C5H10O6, but on the other hand described several derivatives of arabinose carboxylic acid with the formula C7H14O8, since at that time I had no basis, in truth, to dispute the generally accepted formula for arabinose – C6H12O6 – and my analytical results did not contradict either assumption. 1887 HCN arabinose carboxylic acid H+ H2O Na/Hg arabinose mannitol mixture

Kiliani-Fischer Synthesis elongates an aldose Na/Hg D Na/Hg K-F Emil Fischer 1852-1919

Phenylhydrazine - Fischer’s First Chemical Love Osazone crystalline! Emil Fischer 1852-1919

Fischer’s Evidence 1) Glucose Glucaric Diacid “Gulose” HNO3 2) Na (Hg) 1) D 1a) Glucaric Diacid is chiral (both enantiomers known) 2) Glucose & Mannose give same Osazone; Arabinose Gluconic & Mannonic acids Fructose Glucitol & Mannitol Kiliani Na (Hg) 2a) Mannitol & Mannonic Acid are chiral 3) Arabinose Glucose (& Mannose) Xylose Gulose (& Idose?) K-F syn 3a) Arabinose gives active Arabitol and Arabaric Diacid Xylose gives inactive Xylitol and Xylaric Diacid

Fischer’s Evidence 1) Glucose Glucaric Diacid “Gulose” HNO3 2) Na (Hg) 1) D 1a) Glucaric Diacid is chiral (both enantiomers known) 2) Glucose & Mannose give same Osazone; Arabinose Gluconic & Mannonic acids Fructose Glucitol & Mannitol Kiliani Na (Hg) 2a) Mannitol & Mannonic Acid are chiral 3) Arabinose Glucose (& Mannose) Xylose Gulose (& Idose?) K-F syn 3a) Arabinose gives active Arabitol and Arabaric Diacid Xylose gives inactive Xylitol and Xylaric Diacid

REVIEW 1: The Synthesis of Two Unnatural Products (in order to settle a question in the theory of organic chemistry)

Is cyclobutadiene antiaromatic (4n)? h (must be disrotatory) Make it and see. O Presumptive Evidence of its Existence. Spectroscopy? h (2 +2 forbidden thermally) (2 +2 forbidden thermally, but it happens anyway) Diels-Alder + O=C=O very strained

Cram, Tanner, and Thomas (1991) Making & Studying “antiaromatic” Cyclobutadiene Make one molecule per cage mouth O CH CH2 Ph (for solubility) Cram, Tanner, and Thomas (1991)

Preparing Dihydrocinnamaldehyde CH CH3 O CH CH2 Ph O CH Ph O CH Ph

Lucky! Start with Hemisphere 1) “Br+” / -H+ (3 moles) 2) - O-CH2-O bonds by SN2 Ar-O- with CH2BrCl (as mixture with tetra- substituted and two disubstituted analogues) 2) ClCH2 Br Br - How to form the C16 ring? (by chromatography; 5% from tetramer) (OH is activating, o,p-directing) The electrophilic aromatic substitution is reversible, and ultimately the desired “tetramer” stereoisomer precipitates from the equilibrating mixture in 69% yield based on hydrocinnamaldehyde. + H O H H+ Resorcinol + etc. etc. Hydrocinnam- aldehyde Lucky! (from benzaldehyde see above)

Joining Hemispheres - - - 1) Br+/-H+ (3 moles) 2) ~40% HO HO- HO O O-CH2-O bonds by SN2 Ar-O- with CH2BrCl 2) ~40% (1% overall) HO (halogen-metal exchange  more stable “Ar- anion”) HO- HO O - - 3) BuLi - O-B(OR)2 O- Br OH B(OR)2 Li - 4) B(OR)3 (add “Ar- ” to B ; lose RO-) (insert O between C and B. Cf. hydroboration/oxidation; 5) HOO- lose most stable ArO- anion) Note: the purpose of 1,3,4,5 is to “hide” an OH group between the OH groups of resorcinol, and then reveal it. 6) O-CH2-O bonds by SN2 Ar-O- with CH2BrCl

CH3CN are held between adjacent molecules in crystal Stereo Pair X-Ray View JACS, 113, 7717 (1991) (easier to see without a viewer if you make it small) CHCl3 CHCl3 & CH3CN are held between adjacent molecules in crystal CH3CN HC-N(CH3)2 held within molecule. O but lost with t1/2 = 34 hrs at 140°C.

Replace DMF by -Pyranone . O Most shift comes from other rings, still ~1.5 ppm above benzene Antiaromatic upfield shift? . O . . Proton NMR Normal Benzene as guest . above center of 8 benzene rings .

End of Lecture 74 April 27, 20101 Copyright © J. M. McBride 2011. 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

The Benzoin Condensation (prob. 19.90) CN “reverses the polarity” of O=C+ to C- (“umpolung”) also an -activator (benzylic) Ph C OH C N like C=O an -activator what we have: leaving group N C Ph C O C N H H C Ph OH CH3OH H C Ph O H base C N not basic enough to pull off H+.  pKa > 30 C N nucleophile C N - HCN where we’re going: need Ph-C O to attack O=CH-Ph H+

(prepared by this method in 1884) Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis (Cf. p. 1068) Ph-CH2-CH2-CHO H2 / cat (see frame 13) H Cinnamaldehyde (prepared by this method in 1884) H acetaldehyde ,-unsaturated carbonyl  Aldol