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 OCH3 O OH NH2 Doxorubicin (adriamycin) OH

O OH

CH3

Binds to DNA and inhibits the enzyme topoisomerase II

1 and 2 for Ethylene

Orbital Depiction of Ethylene

Orbital Depiction

Hhydrogenation

Carbocation is Resonance Stabilized

CH2=CH-CH=CH2 H CH2=CH-CH-CH3 2o allylic

+ CH2

+ CH CH CH3 Resonance Hybrid

CH2-CH=CH-CH3 1o allylic

Carbocation Stability

Conjugate Addition of HBr

CH2=CH-CH=CH2 Br Br CH2=CH-CH-CH3 CH2-CH=CH-CH3 HBr Br CH2=CH-CHCH3 BrCH2-CH=CH-CH3

1,2- vs. 1,4-Addition

Br H H

CH2=CH-CH=CH2 4 3 2 1

HBr

CH2=CH-CHCH2 BrCH2-CH=CH-CH2 2 1 4 1 kinetic 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 0 C 1,2-addition is favored
o

At 40 C, 1,4-addition is preferred
o

Form more stable carbocation

Allylic Bromination With NBS

O CH2=CHCH3 + N Br in CCl4, h CH2=CHCH2Br + O N H O

O N-Bromosuccinimide

O N O Br

. + Br. N
O

Free Radical Mechanism

Mechanism involves the gradual generation of Br2

i) CH2=CHCH3 + O HBr + N O Br Br

CH2=CHCH2 + HBr Br2

.
O

CH2CH=CH2

N H O

ii)

CH2=CHCH2

CH2CH=CH2

+ Br2

CH2=CHCH2Br + Br

Resonance stabilization leads to possibly several products

NBS, h CCl4 4 products

. .

. .

Br Br + Br major + + Br

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

C C

EWG

cisoid diene

dienophile

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

H2C=CHCN heat CN

H H CN H endo

exo

Endo Addition
H2C=CHCN heat CN

H H H CN

Endo Rule

Identify the Diene and Dienophile that gives the Adducts

O CH3O CH3O O H H H H

O CH3O CH3O O O CH3O CH3O O dienophile

H
2

H H

H retro-D.A.

2 3 4

6 5

+ dienophile

diene

diene

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 with 30 M drug

LS numbers

1,3-Butadiene and Ethylene

Molecular Orbitals

Proper Orbital Overlap

Overlap Must be Constructive

Unsymmetrical Diels-Alder Reactions

OCH3 or CN CN OCH3 OCH3 CN

OCH3

OCH3 or CN CN

OCH3 CN

OCH3

incorrect orientation OCH3 C N

Lewis Acid catalysis in a Diels Alder Reaction

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

O COCH3

AlCl3

AlCl3

COCH3 Lewis acid-base complex

2o Intermediate is Preferred
O AlCl3 O AlCl3 OCH3 2
o

O COCH3

COCH3

major

OCH3 COCH3 O AlCl3 1 O

o

COCH3 AlCl3 minor O

Stereochemistry in endo Addition

CH3 H H H H CH3 CO2CH3 H CH3 CO2CH3 H H CO 2CH3 endo add'n H H H CO 2CH3 H CH3 H

Electrocyclic Reaction in Anti-Tumor Agent

S HO
2

S HO S enzyme
2

O H3COCN O H

O H3COCN H

OR

OR

Calicheamycin (R = sugar)

Diradical Removes H atoms from Deoxyribose in Cancer Cell

Calicheamycin HO S O H3COCN O H HO S O H3COCN OR O

. .

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

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 max = 222 nm

max (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

= 217nm max

= 232nm max

240

HOMO-LUMO Gap
lessens with increased conjugation

Woodward-Fieser Rules
for Predicting max

Base value:
transoid diene 214 nm

Double bond extending conjugation Exocyclic double bond Alkyl group Cl, Br OH, OR

30 nm 5 nm 5 nm 5 nm 6 nm 30 nm 60 nm

cisoid diene 253 nm

SH, SR NH2, NHR, NR2

Predict max in U.V. Spectrum

OCH3

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

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

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