Radicals – Part 1
CH3
Br Br+ +Br
CH3
+ H Br
Explain This Observation...
CH3Br Br Predict: No pi bonds, therefore no reaction
Observation:
CH3
Br
CH3
+ H BrBr Br
hν or heat
Consider: A mixture of Br2 and an alkane...
•Mechanism?
•Why reaction occurs at 3o carbon?
Questions:
Add energy via photons
Lecture Supplement - Radicals -- Page 1
Mechanism
Colorless Red
So mechanism begins with Br2 absorbs hν
•Causes electronic excitation of lone pair electron to σ* orbital
•Weakens σ bond
CH3
Br
CH3
+ H Br+ Br Brhν or heat
= 2 electrons = 1 electron
Colorless – Does not absorb visible light
Red – Absorbs visible light
Br BrBr BrBr Brhν or heat
Br Brhν or heat
Br2Unpaired electron = free radical
Homolytic cleavage = even distribution of bond electrons
Photolysis (photo = light; lysis = destruction) = reaction via light
Radical Fates
Now that I have a radical, what do I do with it?
•How do radicals react?
•What is a radical's motivation?
Radicals react in ways to ...reduce or resolve their electron deficiency. ...become more stable.
Three common ways in which radicals react: The Radical Fates.
Br
Lecture Supplement - Radicals -- Page 2
Radical FatesRadicals desire to become more stable.
Radical Fate #1: Add to a pi bond
•Trade pi bond (weaker) for sigma bond (stronger)
Radical desires one electron to fill octet.
Electron can be provided by ________________________________.
Why not?H2C CH3
Br
H2C CH3
Br
Alternate possibility:
H2C CH3Br
Br
CH3
Radical FatesRadicals desire to become more stable.
Radical Fate #2: Atom transfer
•Usually trades weaker sigma bond for stronger sigma bond
Radical desires one electron to fill octet.
Electron can be provided by ________________________________.
Br
CH3
H Br
Br
CH3
H
+ Br
Lecture Supplement - Radicals -- Page 3
Br Br Br Br
Radical FatesRadicals desire to become more stable.
Radical Fate #3: Radical combination•Driven by completing two open octets, and by gaining a sigma bond
Radical desires one electron to fill octet.
Electron can be provided by ________________________________.
Fact: Radical mechanism steps generally have low ΔG‡
•Therefore one formed, radicals react quickly•[radicals] never becomes very high•Metaphor: Finding a friend (common) versus finding your soul mate (one-of-a-kind)
Conclusion: Radical combination is common uncommon event
Br Br
Back to the Radical Halogenation Mechanism...Our mechanism so far... Br Br
hν or heatBr2
What happens next? Three radical fates...
•Add to a pi bond – no pi bond present
•Atom transfer – possible
•Radical combination – possible but unlikely
What atom does Br steal? Bond change inventory....
Overall reaction is... Therefore next mechanism step is...
Br
CH3
H
CH3Br2 H Br
CH3 CH3
+ H Br
Br Next step?
Lecture Supplement - Radicals -- Page 4
Radical Halogenation Mechanism
Our mechanism so far... Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
Why not... H Br
HHCH2
+ HBr
When choosing between two potential products of a mechanism step, we generally
choose __________________________________.
Radical Structure and Stability
Structure: versus
Pyramidal Trigonal planar
CR RR
C RR
R
Stability
•Central electron-deficient carbon, like a carbocation
Which repels more strongly? One nonbonded electron Two bonded electrons
• So do radicals have same stability trends as carbocations?
R C
R
R
R C
R
R
sp3 carbon sp2 carbon
Lecture Supplement - Radicals -- Page 5
Radical Stability: Degree of Substitution
Carbocations: C
H
H
H
Methyl 1o 2o 3o
C
H
H
H3C C
H
CH3
H3C
Increasing number of electron-donating groupsIncreasing stability
C
CH3
CH3
H3C
Radicals:
Methyl 1o 2o 3o
Increasing number of electron-donating groupsIncreasing stability
H C
H
H
H3C C
H
H
H3C C
H
CH3
H3C C
CH3
CH3
CC
H H
C
H
H H CC
H H
C
H
H H
Radical Stability: Pi Bond Resonance
Carbocations:
Radicals:
Resonance hybrids
C C CH2H
CH2
Conclusion
•A radical does does not gain resonance stabilization from adjacent pi bond.
CC
H H
C
H
H HCC
H H
C
H
H HCC
H H
C
H
H H CC
H H
C
H
H H CC
H H
C
H
H Hδ+ δ+
CC
H H
C
H
H Hδ δ
Lecture Supplement - Radicals -- Page 6
H2C OH H2C OH
H2C OH H2C OH
Radical Stability: Lone Pair Resonance
Carbocations:
Radicals:
Resonance hybrid
Conclusion
•A radical does does not gain resonance stabilization from adjacent lone pair.
H2C OH H2C OH H2C OHδ+ δ+
H2C OHH2C OHH2C OH
FAQ: Radical Rearrangement?
Question: Do radicals rearrange?
Fact: Carbocations may rearrange.
Answer: Radical rearrangement is likely possible never occurs.
2o 3o
2o 3o
H3CCH3
CH3H3C
H3C
CH3
CH3
CH3
H3CCH3
CH3H3C
H3C
CH3
CH3
CH3
?
Lecture Supplement - Radicals -- Page 7
Radical Halogenation Mechanism
Our mechanism so far... Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
Last step: Br
CH3CH3Three ways
Radical Halogenation MechanismWhat is final step of mechanism? Think of radical fates.
Addition to a pi bond – no pi bond present.
Atom transfer – steal Br from another molecule.
Br
CH3CH3
Br Br + Br
Br
CH3CH3
Br H + H
Radical combination –
Br
CH3CH3
BrRadical combination unlikely dueto low concentration of radicals.
Br-Br bond weaker than Br-H bond.
Lecture Supplement - Radicals -- Page 8
Radical Halogenation Mechanism
Complete mechanism:
Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
Br
CH3CH3
Br Br + Br
Chain reaction: A reaction whosemechanism includes one or moresteps that are repeated indefinitely,until the chain is terminated.
One photon yields (in principle) many molecules of product.
Chain Reaction Mechanism Steps
Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
Br
CH3CH3
Br Br + Br
Initiation (I) – starts chain
no radicals → radicals
Propagation (P) – continues chain
radicals → radicals
Termination (T) – ends chain
radicals → no radicals
Lecture Supplement - Radicals -- Page 9
Radicals – Part 2
F C
Cl
F
Cl + O3
N O
Radicals – Part 1 Summary
Mechanism:Radical: Has unpaired electron
Radical fates:
Free radical halogenation:
CH3
Br
CH3
+ H BrBr Br
hν or heat
Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
•Add to pi bond
•Atom transfer
•Radical combination
Radical stability: •Methyl < 1o < 2o < 3o
•Pi bond resonance
•Lone pair resonance
Lecture Supplement - Radicals -- Page 10
Radicals – Part 1 Summary
Mechanism:
Br Brhν or heat
Br2
H Br
CH3 CH3
+ H Br
Br
CH3CH3
Br Br + Br
Chain reaction: A reaction whosemechanism includes one or moresteps that are repeated indefinitely,until the chain is terminated.
Can Other Halogens Be Used?
Highly selective
CH3
Br
CH3
hν or heat
Br2
Less selective
CH3
Cl
CH3
hν or heat
Cl2+
CH3
Cl
+ others
CH3
hν or heat
I2No reaction
Nonselective
CH3F
CF3
hν or heat
F2
F
F
F F
F
F
F
F
FF
Lecture Supplement - Radicals -- Page 11
More on Addition of HBr to Alkenes and Alkynes
Recall:Markovnikov addition
But it's not quite that simple...
C
H3C
H3C
CH2H Br
C
H3C
CH2
BrH3C
H
Mixture
•Impurity = peroxide R-O-O-R
•Adding peroxide causes 100% anti-Markovnikov addition
Kharasch, Mayo (1933):
C
H3C
H3C
CH2H Br
C
H3C
CH2
BrH3C
H
+ C
H3C
CH2
HH3C
Br
C
H3C
H3C
CH2H Br
HO OHC
H3C
CH2
HH3C
BrAnti-Markovnikov is major product"Peroxide effect" observed for HBr only
More on Addition of HBr to Alkenes and Alkynes
Mechanism?
Conclusion: Which adds to pi bond first? Br. H
.
comes from
versus
When choosing between two potential products of a mechanism step, we generally
choose __________________________________.
C
H3C
H3C
CH2
Br
C
H3C
H3C
CH2
Br
C
H3C
CH2
HH3C
Br
•Kharasch and Mayo show it to be a radical chain reaction
•Radical addition to pi bond gives most stable radical
C
H3C
H3C
CH2 C
H3C
H3C
CH2
HH
Lecture Supplement - Radicals -- Page 12
More on Addition of HBr to Alkenes and Alkynes
Mechanism? Radical chain = initiate then propagate
Initiation:
Propagation: Generate Br
HO OH 2 HO
Weak bond
HO H Br HO H + Br
Add to make most stable radical C
H3C
H3C
CH2
Br
C
H3C
H3C
CH2
Br
Last step = termination
propagationC
H3C
H3C
CH2
Br
H Br
C
H3C
H3C
CH2
BrH
+ Br
.
Chain continues
H-X Addition Reactions Orientation SummaryMarkovnikov versus Anti-Markovnikov?
Markovnikov Anti-Markovnikov
C
H3C
H3C
CH2H Br
no peroxideC
H3C
CH2
BrH3C
H
C
H3C
H3C
CH2H Br
C
H3C
CH2
HH3C
Br
RO OR
Markovnikov Anti-Markovnikov
Markovnikov Anti-Markovnikov
Markovnikov Anti-Markovnikov
Only HBr experiences the peroxide effect
C
H3C
H3C
CH2H Cl
no peroxideC
H3C
CH2
ClH3C
H
C
H3C
H3C
CH2H Cl
C
H3C
CH2
ClH3C
H
RO OR
C
H3C
H3C
CH21. BH3
2. HOOH, HOC
H3C
CH2
HH3C
OH
Markovnikov Anti-Markovnikov
Lecture Supplement - Radicals -- Page 13
Dioxygen and Metabolites – Biological Oxidation
O O
Molecular Structure of Dioxygen (O2)
Dioxygen does not have a double bond.
Simple Lewis theory gets it wrong.Lewis theory predicts:
Quantum mechanics predicts:Dioxygen is a diradical.
Quantum mechanics gets it right.O O
Dioxygen and Metabolites – Biological OxidationOrganisms bathed in O2, a diradical. Is this a problem?
O2 is less reactive than most radicals
Electron "leaks" from normal mitochondrial metabolic pathways
Superoxide .
Hydrogen peroxide
Hydroxyl radical
O O
e-
O O
e-
2 "H+"
HO OH
2 HO
•A radical anion•More reactive than O2 but less reactive than HO•Defense against invading microorganisms
•Very aggressive radical•Can attack DNA, lipids, proteins, etc.
Lecture Supplement - Radicals -- Page 14
Dioxygen and Metabolites – Biological Oxidation
Potential for damage to biological structures...
Phospholipid bilayer
•Contains fatty acid alkenes
•Susceptible to attack by HO .
Resonancestabilization
Cross-linkedfatty acids
H
HH +
HOFatty acidalkenes
Radical chaincontinues
Dioxygen and Metabolites – Biological Oxidation
Phospholipid cross-linking can lead to...
•...membranes less flexible, distorted, and damaged
•...reduced solubility lipid → plaque in arteries → atherosclerosis
Biological defenses against radicals: Antioxidants
•Radical scavenger enzymes
Example: Superoxide dismutase (SOD)
•Nonenzymatic defenses
Lipids susceptible to attack by HO because ______________________________
O O2 "H+"
SODO2 + HOOH2
.Therefore an efficient antioxidant has ____________________________________
HO H antiox HO H + antiox Resonance contributors•Reduces reactivity•Slows chain propagation
Lecture Supplement - Radicals -- Page 15
Dioxygen and Metabolites – Biological OxidationLipophilic (Hydrophobic) Antioxidants
α-Tocopherol Main component of vitamin E Ubiquinone (coenzyme Q)
Carotenes β-Carotene is shown
CH3 CH3 CH3
CH3 CH3 CH3
O
HO
CH3
CH3
CH3CH3
CH3
CH3 CH3 CH3CH3O
CH3O
CH3
O
O CH3
H
6-10
Dioxygen and Metabolites – Biological OxidationLipophobic (Hydrophilic) Antioxidants
Ascorbate (vitamin C) Uric acid
O
HO O
O OH
OHH
N
NN
N O
H
O
O
H
H
H
Lecture Supplement - Radicals -- Page 16
Chlorofluorocarbons and Ozone Depletion
Chlorofluorocarbons (CFCs)
•Used as refrigerants, spray can propellants, etc.
•Low chemical reactivity → atmospheric half-life typically 50-100 years
•Released in atmosphere; not removed until stratosphere (8-50 km altitude)
•Crutzen, Rowland, and Molina implicate CFCs in ozone depletion
2 O3 3 O2
hν
•Hazardous at ground level (ozonolysis!)
•Protects against high-energy solar UV in ozone layer (few ppm O3 at 15-35 km altitude)
Ozone (O3)
Chlorofluorocarbons and Ozone Depletion•Reaction occurs on polar atmospheric ice crystals → polar "ozone hole"
Montreal Protocol (1987)
•Agreement to phase out manufacture and release of CFCs and related substances
•Atmosphere will fully recover by 2070
•Nobel Prize in Chemistry 1995 (www.nobelprize.org)
Lecture Supplement - Radicals -- Page 17
Chlorofluorocarbons and Ozone Depletion
Mechanism (simplified):
Chain reaction: On average one Cl radical destroys ~104 O3 before termination
C Cl
Cl
F
F
hνC
Cl
F
F
+ Cl
Freon 12
Cl + O O O Cl O + O O
2 Cl O Cl O O Cl Cl O O + Cl
Cl O O Cl O O+
Nitric Oxide -- NO!N O
Gaseous radical and air pollutant
•Presence in high altitude exhaust implicated in ozone destruction
Physiological effects
•Important for signaling between nerve cells in brain
•Endogenous antibacterial/antiparasitic
•Relaxes blood vessel wall smooth muscle (vasodilation)
Short lived: In vivo half-life ~10 seconds
Nobel Prize in Medicine 1998: Furchgott, Murad, and Ignarro (UCLA)
Lecture Supplement - Radicals -- Page 18
End Exam 2 Coverage
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