Chemistry 125: Lecture 74April 27, 2011

The Structure of Glucoseand

Synthesis of TwoUn-Natural Products This

For copyright notice see final page of this file

Couper1858

CHOH

CHOH

CHOH

CHOH

CHOH

CHOH

HOH

“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)

Carbohydrate(C•HOH)n

γλεῦκοςgleukos

“sweetness”

GlucoseDumas (1838)

“ose” soonbecame the generic suffix for sugars

Grape Sugar (1792)

Carbohydrate(C•HOH)n

CHOH

CHOH

CHOH

CHOH

CHOH

CHOH

C=O

CHOH

CHOH

CHOH

CHOH

CHOH

H

H

aldose(e.g. glucose)

CHOH

C=O

CHOH

CHOH

CHOH

CHOH

H

HCHOH

CHOH

C=O

CHOH

CHOH

CHOH

H

H

ketose(e.g. fructose)

no aldehyde or ketone!

http://riodb01.ibase.aist.go.jp/sdbs/

We know the structure of glucose by spectroscopy

13C-NMR

Crystalline Glucose upon dissolution in D2O 1H-NMR

no aldehyde or ketone

no aldehyde

Cf. J. E. Gurst, J. Chem. Ed. 1003 (1991)

H

H

J7.9Hz

J3.7Hz

gauche

anti

After 1 day in D2O

[a]D = 112°“dextrose”

[a]D = 53°

[a]D = 19°

hemiketalwith H+ or OH-

We know the structure of glucose by spectroscopyand X-ray Diffraction.

But how could they know?

Fructose

Sucrose

Arabinose

reduced

oxidized

GumArabic

Mannitol

Manna

Chirality - van’t Hoff (1877)

Galactose

H+ (1876)

(1873)

Mannose(1888)

HNO3

Heinrich Kiliani

1855-1945

Berlin1885

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:

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

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.

1) HCN

2) HCl (fuming)

1) HCN

2) HCl (fuming)

HI / P

HI / P “which means that my heptanoic acid is identical with [unknown]

ethylpropylacetic acid.”

“does not agree with the description that Hecht gives of the Ca salt of methylbutyacetic acid,”

?

? KOH

(STRONG)

KOH

(STRONG)

NOT from Laevulose!

Kiliani1886

Ca, Ba, Sr, Pbsalts all agree

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.

arabinose mannitol

1887

HCN

arabinosecarboxylic acid

H+

H2O

Na/Hg

mixture

Na/Hg

Emil Fischer1852-1919

Kiliani-Fischer Synthesiselongates an aldose

Na/HgD

K-F

Emil Fischer1852-1919

Phenylhydrazine - Fischer’s First Chemical Love

Osazonecrystalline!

Fischer’s Evidence

1a) Glucaric Diacid is chiral (both enantiomers known)

2a) Mannitol & Mannonic Acid are chiral

3a) Arabinose gives active Arabitol and Arabaric DiacidXylose gives inactive Xylitol and Xylaric Diacid

1) Glucose Glucaric Diacid “Gulose”HNO3

2) Na (Hg)

1) D

2) Glucose & Mannose give same Osazone; Arabinose Gluconic & Mannonic acids

Fructose Glucitol & Mannitol

Kiliani

Na (Hg)

3) Arabinose Glucose (& Mannose)

Xylose Gulose (& Idose?)

K-F syn

K-F syn

Fischer’s Evidence

1a) Glucaric Diacid is chiral (both enantiomers known)

2a) Mannitol & Mannonic Acid are chiral

3a) Arabinose gives active Arabitol and Arabaric DiacidXylose gives inactive Xylitol and Xylaric Diacid

1) Glucose Glucaric Diacid “Gulose”HNO3

2) Na (Hg)

1) D

2) Glucose & Mannose give same Osazone; Arabinose Gluconic & Mannonic acids

Fructose Glucitol & Mannitol

Kiliani

Na (Hg)

3) Arabinose Glucose (& Mannose)

Xylose Gulose (& Idose?)

K-F syn

K-F syn

REVIEW 1:The Synthesis of Two

Unnatural Products

(in order to settle a question in the theory of organic chemistry)

Is cyclobutadiene antiaromatic (4n)?

Diels-Alder

OO

OO

+ O=C=O

h

h

(must be disrotatory)

Make it and see.

(2 +2 forbidden thermally)

very strained

(2 +2 forbidden thermally, but it happens anyway)

Presumptive Evidence of its Existence.

Spectroscopy?

Make one moleculeper cage

Making & Studying“antiaromatic”Cyclobutadiene

(for solubility)

O

CH

CH2

CH2

Ph

mouth

Cram, Tanner, and Thomas (1991)

Preparing Dihydrocinnamaldehyde

O

CH

CH2

CH2

Ph

O

CH

CH

CH

Ph

O

CH

CH3

O

CH

Ph

(as mixture with tetra- substituted and two

disubstituted analogues)

Start with Hemisphere

OH

+

H +

etc. etc.

The electrophilic aromatic substitution is reversible, and

ultimately the desired “tetramer” stereoisomer precipitates from the equilibrating mixture in 69% yield based on hydrocinnamaldehyde.

O-CH2-O bonds by SN2

Ar-O- with CH2BrCl

How to form the C16 ring?

1) “Br+” / -H+ (3 moles)

Br Br Br

2)

--ClCH2

Br

(from benzaldehyde

see above)

Resorcinol

Lucky!

H+

(OH is activating, o,p-directing)

(by chromatography; 5% from tetramer)

Hydrocinnam-aldehyde

Joining Hemispheres1) Br+/-H+ (3 moles)

Br Br Br

3) BuLi

4) B(OR)3

5) HOO-

Li Li LiB(OR)2 B(OR)2 B(OR)2OH OH OH

O-CH2-O bonds by SN2

Ar-O- with CH2BrCl2)

--

~40%(1% overall)HO

O-

O-B(OR)2

HO--O-

6) O-CH2-O bonds by SN2

Ar-O- with CH2BrCl

(add “Ar- ” to B ; lose RO-)

(insert O between C and B. Cf. hydroboration/oxidation;

(halogen-metal exchange

more stable “Ar- 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.

HO-

lose most stable ArO- anion)

CHCl3CHCl3

CHCl3CHCl3

CH3CNCH3CN

CH3CNCH3CN

HC-N(CH3)2 held within molecule.

O

Stereo PairX-Ray View

JACS, 113, 7717 (1991)(easier to see without a

viewer if you make it small)

CHCl3 &CH3CN are

held between adjacent

molecules in crystal

but lost with t1/2 = 34 hrs

at 140°C.

.

. . ... .. .

as guestBenzene

Antiaromaticupfield shift?

Most shift comes fromother rings, still ~1.5ppm above benzene

Normal

Replace DMF by -Pyranone

above center of 8 benzene rings

.

... O

O

O

O

.

... O

O

.

...

Proton NMR

End of Lecture 74April 27, 20101

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The Benzoin Condensation (prob. 19.90)

Ph C

OH

C N

C N

CH 3OH

H C N

nucleophile

like C=O an

-activatorleaving

groupH C Ph

O

also an -activator(benzylic)

Ph C

O

C N

H

H C Ph

OH

N Cbase

- HCN

CN “reverses thepolarity” of O=C+

to C- (“umpolung”)

need Ph-CO

to attack O=CH-Ph

H+

C N

where we’re going:

what we have:

not basic enough topull off H+. pKa > 30

Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis

(Cf. p. 1068)

,-unsaturated carbonyl Aldol

H

acetaldehyde

H

Cinnamaldehyde(prepared by this

method in 1884)

Ph-CH2-CH2-CHO

H2 / cat (see frame 13)