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 O OH OH OH OCH3 O
OH O CH3 NH2 OH Doxorubicin (adriamycin) Binds to DNA and inhibits the enzyme topoisomerase I 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=CH 2 Br HBr CH2=CH-CHCH 3 BrCH2-CH=CH-CH 3 Br Br CH2=CH-CH-CH 3
CH2-CH=CH-CH 3 1,2- vs. 1,4-Addition CH2=CH-CH=CH2 4 3 2 1 HBr Br H
H 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 80oC Thermodynamic Products Cl CH2 H H-Cl 80oC H
CH2 Cl Addition to 1,3,5-Hexatriene Br H 6 4 5 HBr 2
3 1,2 addition 1 Br H 1,4-addition not formed H Br 1,6-addition
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 + O
N Br in CCl4, h CH2=CHCH2Br + O N-Bromosuccinimide N O
O O O Br N H . + Br. N O
Free Radical Mechanism Mechanism involves the gradual generation of Br2 i) CH2=CHCH3 + Br. O HBr + ii) N .
CH2=CHCH2 O . . CH2=CHCH2 O + HBr Br2
Br . CH2CH=CH2 CH2CH=CH2 + N H O
+ Br2 CH2=CHCH2Br . + Br Resonance stabilization leads to possibly several products NBS, h CCl4 4 products
. . . . Br Br + +
+ Br Br major Diels-Alder Reaction a Pericyclic Reaction CH2 H H
C H C CH2 cisoid diene H C C
H EWG C [4+2] cycloaddition H dienophile H
H C C C H H EWG C C
H H adduct H H 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 CH3O
heat H O O H O O
CO2CH3 + HC CCO2CH3 Stereochemistry Bicyclic Adducts endo and exo H2C=CHCN
CN heat H H CN H endo exo Endo Addition heat
H2C=CHCN H H H CN CN Identify the Diene and Dienophile that gives the Adducts O
H CH3O CH3O O H H H O
6 5 H 1 2 CH3O CH3O O 4
3 H H H retro-D.A. O CH3O CH3O O dienophile
1 2 + 6 3 4 diene diene
+ 5 dienophile Two Phosphatase Inhibitors O O O
O O S O O CH3 CH3 Cantharidin
LS-5 H H A Radiosensitizer HOOC O O OH
O OH H H OH O O H Okadaic acid
O H O OH Synthesis of LS-5 O O O
O O O O + furan O maleic anhydride
in THF room temp. O O O O S 1) H2, 1%Pt/C
O O 2) Na2S . 9H2O O exo adduct 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 OCH3 OCH3
CN or CN CN OCH3 OCH3 OCH3 CN
or CN OCH3 C N incorrect orientation OCH3
C N CN Lewis Acid catalysis in a Diels Alder Reaction O O COCH3 COCH3
+ no cat. 90% with AlCl 3 cat. 98% O COCH3 AlCl3 10% 2%
O AlCl3 COCH3 Lewis acid-base complex COCH3 O 2o Intermediate is Preferred O
AlCl3 O COCH3 O AlCl3 COCH3 OCH3 major
o 2 OCH3 COCH3 O AlCl3 O o 1
COCH3 AlCl3 minor O Stereochemistry in endo Addition CH3 H H
H CO2CH3 H endo add'n H H CH3 H H
H H CO2CH3 H CH3 H CH3 CO2CH3 CO2CH3
Electrocyclic Reaction in Anti-Tumor Agent S S HO S HO S 2
2 enzyme O 9 H3COCN O H 7
O 9 H3COCN OR Calicheamycin (R = sugar) O H 7
OR Diradical Removes H atoms from Deoxyribose in Cancer Cell Calicheamycin HO HO S O
S . O H3COCN O H H3COCN OR
O . OR H . o 200 C .
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 Retro Diels-Alder, followed by Diels-Alder 2 o
b.p. = 40 C dicyclopentadiene O H H heat O O
O Intramolecular photochemical [2+2] cycloaddion H H O O h [2+2]
H H O O Adjacent Thymines (Ts) in DNA Susceptible to [2+2] cycloaddition in sunlight (UV-B, 290-320 nm) sugar sugar O
O NH HN O O N N H
H O h O NH HN O N
N H H O prevents DNA replication 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. max = 217nm max = 232nm 217 220 223
226 227 232 240 HOMO-LUMO Gap lessens with increased conjugation Woodward-Fieser Rules for Predicting max
Base value: Double bond extending conjugation Exocyclic double bond 30 nm Alkyl group 5 nm Cl, Br
5 nm OH, OR 6 nm SH, SR 30 nm NH2, NHR, NR2 60 nm
transoid diene 214 nm cisoid diene 253 nm 5 nm 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
