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Conjugated Dienes and U.V.

Spectroscopy

Some Dienes

Some Conjugated Molecules


O H

Vitamin A O

Benzene

Cyclohex-2-enone

Prevents DNA from Unraveling


O OH O OH OH OCH3 O OH NH2 OH Doxorubicin (adriamycin)

CH3

Binds to DNA and inhibits the enzyme topoisomerase

Y1 and Y2 for Ethylene

Orbital Depiction of Ethylene

Orbital Depiction

DHhydrogenation

Carbocation is Resonance Stabilized


H CH2=CH-CH=CH 2 CH2=CH-CH-CH 3 2o allylic

+ CH2

+ CH CH CH3 Resonance Hybrid

CH2-CH=CH-CH 3 1o allylic

Carbocation Stability

Conjugate Addition of HBr


Br CH2=CH-CH=CH 2 Br Br CH2=CH-CH-CH 3 CH2-CH=CH-CH 3 HBr CH2=CH-CHCH 3 BrCH 2-CH=CH-CH 3

1,2- vs. 1,4-Addition


Br CH2=CH-CH=CH 2 4 3 2 1 HBr H H

CH2=CH-CHCH 2 BrCH 2-CH=CH-CH 2 2 1 4 1 k inetic thermodynamic forms more rapidly is more stable

Kinetic and Thermodynamic Products

Kinetic vs. Thermodynamic Control

2 Different 1,4- Products Form

H-Cl 80 oC

Thermodynamic Products
Cl CH2 H H-Cl 80oC H CH2 Cl

Addition to 1,3,5-Hexatriene
Br H
6 5 4 3 2 1

HBr

1,2 addition Br H 1,4-addition not formed Br 1,6-addition H

At 0oC 1,2-addition is favored

At 40oC, 1,4-addition is preferred

Form more stable carbocation

Allylic Bromination With NBS


O CH2=CHCH 3 + N Br in CCl4, h CH2=CHCH 2Br + O N H O

O N-Bromosuccinimide

O N Br O

. + N
O

Br

Free Radical Mechanism

Mechanism involves the gradual generation of Br2


i) CH2=CHCH 3 + O HBr + N Br O Br

CH2=CHCH 2 + HBr

.
O

CH2CH=CH 2

Br 2 +

N H O

ii)

CH2=CHCH 2

CH2CH=CH 2

+ Br 2

CH2=CHCH 2Br + Br

Resonance stabilization leads to possibly several products


NBS, h CCl4 4 products

. .

. .

Br Br + Br major + + Br

Diels-Alder Reaction
a Pericyclic Reaction
CH2 C H C CH2 H EWG C C H dienophile [4+2] cycloaddition H H H C C C C H H C C H EWG H

cisoid diene

H H adduct

EWG

Dienophiles Must be Electron Deficient


Electron-withdrawing groups typically have sp2 or sp atom attached to bond e.g. O C C C N R C R = H, alkyl, OH, OR, Cl EWG

O CH3O O O heat CH3O

O O

HC

CCO2CH3

CO2CH3

Stereochemistry

Bicyclic Adducts endo and exo


CN H2C=CHCN heat

H H CN H endo

exo

Endo Addition
CN H2C=CHCN heat

H H CN H

Endo Rule

Identify the Diene and Dienophile that gives the Adducts


O CH3O CH3O O H H H H

O CH3O CH3O O

H
2

H H

H retro-D.A.

O
1

CH3O CH3O O dienophile

2 3 4

+
5

diene

diene

dienophile

Two Phosphatase Inhibitors


O O O CH3 CH3 Cantharidin O LS-5 H H O O S O

A Radiosensitizer
OH O H Okadaic acid O H O OH

HOOC OH

O O OH H O

Synthesis of LS-5
O + furan maleic anhydride O O O O O O O

in THF room temp. O O S O 1) H2, 1%Pt/C 2) Na2S . 9H2O exo adduct O O O O

Cytotoxicity
of asynchronous DU-145 prostate cancer cells exposed to drug for o 2-h at 37 C Cantharidin Cantharidic acid LS-5

Survival Curves
HT-29 colon cancer cells Irradiated after 2-h exposure to 2 M drug

Control (no drug) LS-1 LS-2 LS-5 LS-5 (1 M)

Survival Curves of G1 phase HT-29 cells after 2-h exposure to LS-5

Control (no drug) 0.2 M 0.5 M 1.0 M 2.0 M

Radiation Inactivation of DU-145 cells by 4 Gy Cs-137 after treatment w ith 30 M drug

LS numbers

1,3-Butadiene and Ethylene


Molecular Orbitals

Proper Orbital Overlap

Overlap Must be Constructive

Unsymmetrical Diels-Alder Reactions


OCH3 D or CN CN OCH3 OCH3 CN

OCH3 D

OCH3 or CN CN

OCH3 CN

OCH3

C N incorrect orientation OCH3 N C

Lewis Acid catalysis in a Diels Alder Reaction


O COCH3 D O COCH3 + no cat. 90% with AlCl 3 cat. 98% 10% 2% COCH3 O

O COCH3

AlCl3 AlCl 3 O COCH3

Lewis acid-base complex

o 2

Intermediate is Preferred
AlCl3 O AlCl3 OCH3 2
o

O COCH3

O COCH3

major

OCH3 COCH3 O AlCl3 1 O


o

COCH3 AlCl3 minor O

Stereochemistry in endo Addition


CH3 H H H H H H H CH3 CO2CH3 CH3 CO2CH3 CO2CH3 H endo add'n H H H CO2CH3 H CH3

Electrocyclic Reaction in Anti-Tumor Agent


S HO
2

S HO S
2

enzyme O H3COCN O H OR
9 7

O H3COCN O H

OR

Calicheamycin(R = sugar)

Diradical Removes H atoms from Deoxyribose in Cancer Cell


Calicheamycin HO S HO S

O H3COCN O H OR

O H3COCN O H

.
OR

.
200 C
o

[2+2] Cycloaddion is Forbidden

Photochemical [2+2] Cycloaddition Need to Irradiate

Suprafacial Allowed

Antarafacial - Forbidden

[4+2] is Suprafacial, hence Allowed

Cycloaddition Reactions can be Planned Based on the Number of Pairs of e-s that Move

Formation of Cyclobutanes
h [2+2] H2C CH2

A [4+6] Cycloaddition (odd # pairs of e s move) Thermally Allowed

Retro Diels-Alder, followed by Diels-Alder


D 2 b.p. = 40 C H H
o

dicyclopentadiene O heat

Intramolecular photochemical [2+2] cycloaddion


H H H H O O

h [2+2]

Ultraviolet Spectroscopy

The absorption of a 171-nm photon excites an electron from the p bonding MO of ethylene to the p* antibonding MO.

Conjugated Dienes Absorb Energy in UV Region

UV Spectrum of Isoprene lmax = 222 nm

lmax (nm)

Conjugation lowers the energy differences between the HOMO and LUMO energy levels, and so conjugated dienes absorb at longer wavelengths than isolated dienes, and trienes absorb at longer wavelengths than dienes, etc. Alkyl group substitution on double bonds also causes absorption to occur at longer wavelengths.

217 220 223

226

227

232

lmax = 217nm

lmax = 232nm

240

HOMO-LUMO Gap
lessens with increased conjugation

Woodward-Fieser Rules
for Predicting lmax

Base value:

Double bond extending conjugation Exocyclic double bond

30 nm 5 nm

transoid diene 214 nm

Alkyl group
Cl, Br OH, OR

5 nm
5 nm 6 nm

cisoid diene

253 nm

SH, SR
NH2, NHR, NR2

30 nm
60 nm

Predict lmax in U.V. Spectrum

OCH3

Determination of lmax
Base: 214 nm R groups: 4 x 5 = 20 nm exocyclic db = 5 nm predicted lmax= 239 nm

Determination of lmax
OCH3 Base: 214 nm double bond ext. conj. = 30 nm OR group = 6 nm R group = 5 nm predicted lmax = 255 nm

Determination of lmax
Base: 253 nm db ext. conj. = 30 R groups: 3 x 5 = 15 exocyclic db = 5 predicted lmax =303 nm