Radical Reaction Objectives:

Radical Reaction Objectives:
Regioselectivity and Application in Synthesis Mechanism of simple alkane and allylic compound Self reading: Thermodynamics of free radical reactions Free radicals in environment and industry Klein, Organic Chemistry 2e

Free Radicals Free radicals form when bonds break homolytically
Single-barbed or fishhook arrow used to show the single electron movement Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Bond Dissociation Energy
BDE (kJ/mol) is energy required to break bond homolytically Free radicals form when bonds break homolytically Free radical often forms from low BDE bonds Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

C+ (sp2), C:- (sp3), Radical
Free radicals can be thought of as sp2 hybridized or quickly interconverting sp3 hybridized. Free radicals resemble carbocation. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Free Radical Stability
Free radicals do not have a formal charge but are unstable because of an incomplete octet Similar to Carbocation, Groups that can push (donate) electrons toward the free radical will help to stabilize it, such as hyperconjugation Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Free Radical Stability affects BDE
Because of the relative stability of carbon free radicals, the bond dissociation energies ranks as below Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Resonance Stabilize Free Radical
Remember fishhook arrow as only ONE electron Converging fishhooks for “forming a bond” (single to double), diverging fishhooks for “breaking a bond” (double to single). Example: The resonance hybrid for an allyl radical Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Practice: Resonance for Benzylic Radical
The benzylic radical is a hybrid that consists of 4 contributors. Draw the remaining contributors Draw the hybrid Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Resonance Stabilization of Radical
Resonance stabilizes radical more than hyperconjugation Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Vinylic free radical: NO Resonance
Vinylic free radicals are especially unstable No resonance stabilization Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

2 Radical Electron Movement
Free radical electron movement is quite different from electron movement in ionic reactions For example, free radicals don’t undergo rearrangement There are SIX key arrow-pushing patterns that we will discuss Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical Electron in Rxn
Homolytic Cleavage: initiated by light or heat Addition to a pi bond Hydrogen abstraction: NOT the same as proton transfer Halogen abstraction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical Electron in Rxn
Elimination: the radical from the α carbon is pushed toward the β carbon to eliminate a group on the β carbon (reverse of addition to a pi bond) The –X group is NOT a leaving group. WHY? Coupling: the reverse of homolytic cleavage Note that radical electron movement generally involves 2 or 3 fishhook arrows Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Connection among the 6 Radical rxns
Note the reversibility of radical processes Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical Rxn Patterns Radical electron movement is generally classified as either Initiation, Termination, or Propagation Termination Initiation Initiation occurs when radicals are created, from an unstable bond, such as X-X, O-O bond Termination occurs when radicals are destroyed, the reverse of initiation. Typically forming a stable bond, such as C-X, C-O, C-C, C-H bond. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

3. Radical Rxn: Chlorination of Methane
Bond change: C-H + Cl-Cl  C-Cl + H-Cl. Exothermic. Initiation: homolytic dissociation of Cl-Cl bond under radiation (hv) BDECl-Cl = 243 kJ/mol vs. BDEC-H = 410 kcal/mol Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Propagation in Alkane Chlorination
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Termination of Alkane Chlorination
All free radicals as intermediates may undergo termination. But termination reactions happen less often than propagation reactions due low [radical]. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Chlorination of Methane
The propagation steps give the net reaction Initiation produces a small amount Cl• radical H abstraction consumes Cl• radical Cl abstraction generates a Cl• radical, which can go on to start another H abstraction Propagation steps are self-sustaining Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Alkane Chlorination as Chain Rxn
Reactions that have self-sustaining propagation steps are called chain reactions Chain reaction: the products from one step are reactants for a different step in the mechanism Polychlorination is difficult to prevent, especially when an excess of Cl2 is present. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical Initiators An initiator starts a free radical chain reaction
Initiator w/ low BDE initiates reactions readily The acyl peroxide will be effective at 80 °C Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

O2 as Radical Inhibitors
Inhibitors act in a reaction to scavenge free radicals to stop chain reaction processes. Oxygen molecules as a diradical, able to react readily with other radicals (Termination). Use arrows to show the process Removal of oxygen may stop oxygen from inhibiting a desired chain reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical Inhibitor: Hydroquinone
Quinone: “Diketone” on benzene ring Hydroquinone is also often used as a radical inhibitor Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

5 Halogenation Regioselectivity
With substrates more complex than ethane, multiple monohalogenation products are possible If the halogen were indiscriminant, predict the product ratio? 1:3. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Halogenation Regioselectivity
For the CHLORINATION process, the actual product distribution favors 2-chloropropane over 1-chloropropane Secondary C-H is preferred over primary C-H Recall the stability of carbocation in terms of alkyl groups Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Stability of free radical in Regioselectivity
In one reaction, a 1° free radical forms, and in the other a 2° radical forms Chlorination on 2° carbon is both thermodynamically or kinetically favored Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Bromination Regioselectivity
For the BROMINATION process, the product distribution vastly favors 2-bromopropane over 1-bromopropane, thanks to the stability of free radical determines regioselectivity Useful in synthesis Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Regioselectivity: Chloriantion vs. Bromination
Bromination at the 3° position happens 1600 times more often than at the 1° position Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Halogenation Regioselectivity

Practice: Chlorination of Alkane
In the chlorination of 2-methylpropane, predict the major products Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Application: Halogenation Regioselectivity
Ignoring possible addition products for now, draw the structure for EVERY possible monobromination product for the reaction below Rank the products in order from most major to most minor Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

6 Halogenation Stereochemistry
The halogenation of butane or more complex alkanes forms a new chirality center 2-chlorobutane will form as a racemic mixture The planar free radical is responsible for the stereochemical outcome. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Halogenation Stereochemistry
Whether the free radical carbon is sp2 or a rapidly interconverting sp3, the halogen abstraction will occur on either side of the plane with equal probability sp2 hybridized Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Practice: Halogenation Stereochemistry
Draw all of the monosubstituted products that would form in the halogenation below including all stereoisomers Classify any stereoisomer pairs as either enantiomers or diasteriomers Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Synthetic Utility of Halogenation
Radical chlorination and bromination are both useful processes Bromination is more selective if one site with substituents. Chlorination can be useful with highly symmetrical substrates Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Limited Utility of Halogenation
Temperature can be used to help avoid polysubstitution. It is difficult to avoid polysubstitution. The synthetic utility of halogenation is limited Chlorination is difficult to control Bromination requires a substrate with 1 site that is significantly more reactive than all others Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Alkane Halogenation as Precursor
Synthesizing a target molecule from an alkane is challenging because of its limited reactivity Often halogenation is the best option Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

7 Allylic Halogenation When an C=C double bond is present it affects the regioselectivity of the halogenation reaction Given the bond dissociation energies below, which position of cyclohexene will be most reactive toward halogenation? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Resonance of Allylic free radical
When an allylic hydrogen is abstracted, it leaves behind an allylic free radical that is stabilized by resonance Based on the high selectivity of bromination that we discussed, you might expect bromination to occur as shown below Addition (halogenation) competes Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Allylic Halogenation with NBS
To avoid the competing halogenation addition reaction, NBS can be used to supply Br• radicals Initiation by Heat or light Resonance stabilizes the succinimide radical Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Mechanism of Bromination with NBS
Propagation produces new Br• radicals to continue the chain reaction The amount of Br-Br (from termination of bromine radical) in solution is minimal, so the competing addition reaction is minimized Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Regenaration of succinimide radical
The succinimide radical from initiation step can also undergo propagation when it collides with an H-Br molecule to form succinimide and Br + H-Br Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Practice: Allylic Halogenation with NBS
Give a mechanism that explains the following product distribution. Hint: resonance Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

4 Halogenation Thermodynamics
Strongly forward reaction require large negative ΔG In a halogenation reaction, -TΔS have negligible effect on the sign of ΔG. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Enthalpy change in Halogenation

Fluorination and Iodination 
Fluorination is so exothermic that it is impractical. Iodination is nonspontaneous, so it is not product favored Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Chlorination vs. Bromination 
Consider chlorination and bromination in more detail Chlorination is more product favored than bromination Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Chlorination vs. Bromination
Chlorination has fast initiation, both steps exothermic, both kinetically and thermodynamically favored Bromination has slow endothermic initiation First step is endothermic Both steps are exothermic Second step is exothermic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Hammond Postulate on Regioselectivity
Energy diagram on H abstraction: Hammond postulate indicates species with similar in energy are similar in structure. Bromination better selectivity as TS close to product Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

TS in H abstration in Halogenation

TS in H abstraction Bromination: TS is more similar to product, the free radical, thus the carbon must be able to stabilize a large partial radical (resonance and hyperconjugation 3 > 2 > 1) Chlorination: TS is more similar to reactant, the alkane, thus the carbon does not carry as much of a partial radical. Radical stability is not as important in selectivity Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Regioselectivity in H abstration: Bromination > Chlorination

Additional Practice Problems
Show all significant resonance contributors and a resonance hybrid for the following molecule. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.8 Atmospheric Chemistry and O3
Ozone is both created and destroyed in the upper atmosphere O3 molecules absorb harmful UV radiation O3 molecules are recycled as heat energy is released Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

For this process to be spontaneous, the entropy of the universe must increase Heat is a more disordered form of energy than light. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

O3 depletion (about 6% each year) remains a serious health and environmental issue Compounds that are most destructive to the ozone layer Are stable enough to reach the upper atmosphere Form free radicals that interfere with the O3 recycling process Chlorofluorocarbons (CFCs) fit both criteria Atmosphere O3 is vital for protection, but what effect does O3 have at the earth’s surface? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

CFC substitutes that generally decompose before reaching the O3 layer include hydrochlorofluorocarbons Hydrofluorocarbons don’t even form the chlorine radicals that interfere with the O3 cycle Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.8 Combustion and Firefighting
Like most reactions, combustion involves breaking bonds and forming new bonds A fuel is heated with the necessary Eact to break bonds (C-C, C-H, and O=O) homolytically The resulting free radicals join together to form new O-H and C=O bonds Why does the process release energy overall? What types of chemicals might be used in fire extinguishers to inhibit the process? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Water deprives the fire of the Eact needed by absorbing the energy CO2 and Argon gas deprive the fire of needed oxygen Halons are very effective fire-suppression agents Halons suppress combustion in three main ways Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Halons suppress combustion in three main ways As a gas, they can smother the fire and deprive it of O2 They absorb some of the Eact for the fire by undergoing homolytic cleavage The free radicals produced can combine with C• and H• free radicals to terminate the combustion chain reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

How do you think the use of halons to fight fires affects the ozone layer? FM-200 is an alternative firefighting agent Practice with conceptual checkpoint 11.18 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Autooxidation Autooxidation is the process by which compounds react with molecular oxygen The process is generally very slow Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Autooxidation Mechanism
The mechanism illustrates the need for a more refined definition of initiation and propagation. HOW? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Autooxidation Mechanism
Propagation can be more precisely defined as the steps that add together to give the net chemical equation Steps in the mechanism that are not part of the net equation must be either initiation or termination Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Autooxidation Some compounds such as ethers are particularly susceptible to autooxidation Because hydroperoxides can be explosive, ethers like diethyl ether must not be stored for long periods of time They should be dated and used in a timely fashion Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Autooxidation Light accelerates the autooxidation process
Dark containers are often used to store many chemicals such as vitamins In the absence of light, autooxidation is usually a slow process Compounds that can form a relatively stable C• radical upon H abstraction are especially susceptible to autooxidation. WHY? Consider the autooxidation of compounds with allylic or benzylic hydrogen atoms Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Antioxidants Triglycerides are important to a healthy diet
Autooxidation can occur at the allylic positions causing the food to become rancid and toxic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Antioxidants Preservatives can undergo H abstraction to quench the C• radicals that form in the first step of autooxidation One molecule of BHT can prevent thousands of autooxidation reactions by stopping the chain reaction How does BHT’s structure make it good at taking on a free radical? Consider resonance and sterics Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.9 Natural Antioxidants Vitamins C is hydrophilic
Vitamin E is hydrophobic What parts of the body do these vitamins protect? For each vitamin, show its oxidation mechanism, and explain how that protects the body from autooxidation Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.10 Anti-Markovnikov Addition
We learned in chapter 9 that H-X will add across a C=C double bond with anti-Markovnikov regioselectivity when peroxides are present Now that we have discussed free radicals, we can explain the mechanism for the anti-Markovnikov addition Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

The Br• radical reacts to give the more stable C• radical A 3° radical forms through a lower TS than a 2° radical Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Most of the radicals in solution at any given moment will be Br• radical. WHY? Give some examples of other termination steps that might occur but that would be less common Go back through each step in the mechanism to explain the ΔH value for each step Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.10 Addition Thermodynamics
Anti-Markovnikov radical addition of HBr is generally spontaneous (product favored) Yet, radical addition of HCl and HI are generally nonspontaneous (reactant favored) On the next few slides, we will examine the thermodynamics of each propagation step Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Explain the sign (+/-) for the entropy term in each process Will the entropy change favor products or reactants? WHY? The enthalpy change is affected most by the relative stability of the two radical species Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

The HI reaction will never favor products. WHY? How can the temperature be adjusted to favor products for the HCl and HBr reaction? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

For the second propagation step, why is the entropy term approximately zero? What small differences in entropy between products and reactants might account for entropy changes being slightly + or -? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

For HCl , the second propagation step will not be product favored. WHY? HBr is the only reactant that favors product formation for both propagation steps Might the overall propagation involving HCl be product favored if the –ΔG of step 1 outweighs the +ΔG of step 2? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.10 Addition Stereochemistry
Addition reactions often form a new chirality center Recall that at least 1 reagent in the reaction must be chiral for the reaction to be stereoselective Predicts the product distribution for the reaction below and explain the stereochemical outcome Practice with SkillBuilder 11.8 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.11 Radical Polymerization
In chapter 9, we learned how some ionic polymerizations occur Free radical conditions are also frequently used to form polymers Recall that a polymerization process joins together many small units called monomers in a long chain Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical polymerizations generally proceed through a chain reaction mechanism Note how the sum of the propagation steps yields the overall reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Radical polymerizations generally produce chains of monomers with a wide distribution of lengths How might experimental conditions be optimized to control the average length of the chains? Because the mechanism we just learned proceeds through 1° carbon free radical intermediates, it is usually not facile In chapter 27, we will discuss specialized catalysts that can be used to control such polymerization reactions Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Branching is common in some radical polymerizations Branching makes polymer materials more flexible such as a polyethylene squeeze bottle When catalysts are used to minimize branching, more rigid materials are produced such as the squeeze bottle cap Why does branching affect rigidity? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.12 Radical Petroleum Processes
Recall the cracking and reforming processes from chapters 4 and 8 Crude oil is cracked to produce smaller alkanes and alkenes Reforming increases branching. Propose a mechanism Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.4 Halogenation Thermodynamics
Which step in the mechanism is the slow step? Which reaction has a faster rate? Which is more product favored? First step is endothermic Both steps are exothermic Second step is exothermic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.4 Halogenation Thermodynamics
Is the key step in the bromination mechanism kinetically or thermodynamically controlled? WHY? First step is endothermic Both steps are exothermic Second step is exothermic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

11.5 Halogenation Regioselectivity
Focus on the H abstraction step, and consider the Hammond postulate: species on the energy diagram that are similar in energy are similar in structure Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

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