1. 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

2. “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

3. 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

4. We know the structure of glucose by spectroscopy
no aldehyde or ketone!

5. 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 (1991)

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

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

8. Heinrich Kiliani

9. 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

10. 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-

11. 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

12. Kiliani-Fischer Synthesis
elongates an aldose
Na/Hg D
Na/Hg
K-F
Emil Fischer

13. Phenylhydrazine - Fischer’s First Chemical Love
Osazone
crystalline!
Emil Fischer

14. 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

15. 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

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

17. 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

18. 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)

19. Preparing DihydrocinnamaldehydeCH
CH3 O CH
CH2 Ph O CH Ph O CH Ph

20. 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)

21. 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

22. 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.

23. 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 .

24. End of Lecture 74 April 27, 20101
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25. 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+

26. (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