1. Radical Chain Reactions

2. Radicals
A radical is a reactive intermediate with a single unpaired electron, formed by homolysis of a covalent bond.
A radical contains an atom that does not have an octet of electrons.
Half-headed arrows are used to show the movement of electrons in radical processes.

3. Halogenation of Alkanes
In the presence of heat or light, alkanes react with halogens to form alkyl halides.
Halogenation of alkanes is a radical substitution reaction.
Halogenation of alkanes is only useful with Cl2 or Br2. Reaction with F2 is too violent, and reaction with I2 is too slow to be useful.
Example: Monochlorination of Methane

4. Control of Chlorination
When a single hydrogen atom on a carbon has been replaced by a halogen atom, monohalogenation has taken place.
When excess halogen is used, it is possible to replace more than one hydrogen atom on a single carbon with halogen atoms.
Monohalogenation can be achieved experimentally by adding halogen X2 to an excess of alkane.

5. Mechanism Radical halogenation has three distinct parts.
A mechanism such as radical halogenation that involves two or more repeating steps is called a chain mechanism.
The most important steps of radical halogenation are those that lead to product formation—the propagation steps.

6. Evidence for a Radical Mechanism
Three facts about halogenation suggest that the mechanism involves radical, not ionic, intermediates:

7. Radical Inhibitors
Compounds that prevent radical reactions from occurring are called radical inhibitors or radical scavengers. Besides O2, vitamin E and other related compounds are radical scavengers.
Oxygen (O2)- is a diradical in its ground state electronic configuration.
In halogenation reactions, O2 is believed to react with the methyl radical (CH3∙) to form the CH3OO∙ radical which is far less reactive than CH3∙. One O2 molecule breaks the chain and prevents formation of chlorinated product , i. e. CH3Cl.

8. Chlorination of Propane
Note that CH3CH2CH3 has six 10 hydrogens and only two 20 hydrogens, so the expected product ratio of CH3CH2CH2Cl to (CH3)2CHCl (assuming all hydrogens are equally reactive) is 3:1.
Product Distribution:
Chlorination of CH3CH2CH3 affords a 1:1 mixture of CH3CH2CH2Cl and (CH3)2CHCl.

9. Formation of 2° & 1° Carbon Radicals from Propane
Since the observed ratio between CH3CH2CH2Cl and (CH3)2CHCl is 1:1, the 20 C—H bonds must be more reactive than the 10 C—H bonds.
Thus, when alkanes react with Cl2, a mixture of products results, with more product formed by cleavage of the weaker C—H bond than you would expect on statistical grounds.

10. Carbon Radicals

11. Carbon Radicals
A carbon radical is sp2 hybridized and trigonal planar, like sp2 hybridized carbocations.
The unhybridized p orbital contains the unpaired electron and extends above and below the trigonal planar carbon.

12. Relative Stability of Carbon Radicals

13. Inductive Effects Also explained in the organic text: (7.14A page 248)
Alkyl groups stabilize the electron deficient carbon radical by donation of electron density through the C-C s bonds.
Alkyl groups are versatile and may donate electron density or withdrawal electron density thourgh the C-C s bonds.
Thus, neighboring alkyl groups my stabilize carbon radicals, carbocations, and carbanions.
Example:

14. Hyperconjugation Explained in Text 7.14B page 249.
An electron deficient carbon is believed to be stabilized through orbital overlap between the electron rich s bonding molecular orbitals from an adjacent alkyl group with the half filled p orbital of the carbon radical.
Methyl radicals are not stabilized via hyperconjugation!
Hyperconjugation can not happen in a methyl radical b/c the hydrogen s orbitals are not of the right symmetry to overlap with the half filled p orbital of the carbon radical.

15. Halogenation Rxns
Practice Rxns:
Cl2, hn
Cl2, hn
Cl2, hn

17. Energy Diagrams

18. Bond Dissociation Energy
The energy absorbed or released in any reaction, symbolized by Ho, is called the enthalpy change or heat of reaction.
Bond dissociation energy is the Ho for a specific kind of reaction—the homolysis of a covalent bond to form two radicals.

19. Bond Dissociation Energy
Because bond breaking requires energy, bond dissociation energies are always positive numbers, and homolysis is always endothermic.
Conversely, bond formation always releases energy, and thus is always exothermic. For example, the H—H bond requires +104 kcal/mol to cleave and releases –104 kcal/mol when formed.

20. Bond Dissociation Energy
Comparing bond dissociation energies is equivalent to comparing bond strength.
The stronger the bond, the higher its bond dissociation energy.
Bond dissociation energies decrease down a column of the periodic table.
Generally, shorter bonds are stronger bonds.

21. Enthalpy Change (DH°) in a Rxn.
Bond dissociation energies are used to calculate the enthalpy change (H0) in a reaction in which several bonds are broken and formed.

22. Bond dissociation energies have two important limitations.
Bond dissociation energies present overall energy changes only. They reveal nothing about the reaction mechanism or how fast a reaction proceeds.
Bond dissociation energies are determined for reactions in the gas phase, whereas most organic reactions occur in a liquid solvent where solvation energy contributes to the overall enthalpy of a reaction.
Bond dissociation energies are imperfect indicators of energy changes in a reaction. However, using bond dissociation energies to calculate H0 gives a useful approximation of the energy changes that occur when bonds are broken and formed in a reaction.

23. Enthalpy (DH) of Halogenation Reactions

24. Energy Diagrams
An energy diagram is a schematic representation of the energy changes that take place as reactants are converted to products.
An energy diagram plots the energy on the y axis versus the progress of reaction, often labeled as the reaction coordinate, on the x axis.
The energy difference between reactants and products is H0. If the products are lower in energy than the reactants, the reaction is exothermic and energy is released. If the products are higher in energy than the reactants, the reaction is endothermic and energy is consumed.
The unstable energy maximum as a chemical reaction proceeds from reactants to products is called the transition state. The transition state species can never be isolated.
The energy difference between the transition state and the starting material is called the energy of activation, Ea.

25. Exothermic Reaction For the general reaction:
The energy diagram would be shown as:

26. Quiz #2
Thursday, October 12th

27. Transition State
The energy of activation is the minimum amount of energy needed to break the bonds in the reactants.
The larger the Ea, the greater the amount of energy that is needed to break bonds, and the slower the reaction rate.
The structure of the transition state is somewhere between the structures of the starting material and product. Any bond that is partially formed or broken is drawn with a dashed line. Any atom that gains or loses a charge contains a partial charge in the transition state.
Transition states are drawn in brackets, with a superscript double dagger (‡).

28. Two Different Exothermic Reactions

29. Comparing Reactions

30. Energy Diagram for a Chlorination Reaction

31. Kinetics Kinetics is the study of reaction rates.
Recall that Ea is the energy barrier that must be exceeded for reactants to be converted to products.

32. Catalysts
Some reactions do not proceed at a reasonable rate unless a catalyst is added.
A catalyst is a substance that speeds up the rate of a reaction. It is recovered unchanged in a reaction, and it does not appear in the product.

33. Chlorination vs. Bromination

34. Chlorination versus Bromination
Although alkanes undergo radical substitutions with both Cl2 and Br2, chlorination and bromination exhibit two important differences.
Chlorination is faster than bromination.
Chlorination is unselective, yielding a mixture of products, but bromination is often selective, yielding one major product.

36. Energetics of the Bromination Rxn.
The differences in chlorination and bromination can be explained by considering the energetics of each type of reaction.
Calculating the H0 using bond dissociation energies reveals that abstraction of a 10 or 20 hydrogen by Br• is endothermic, but it takes less energy to form the more stable 20 radical.

37. Transition State in the Bromination of Propane
Conclusion: Because the rate-determining step is endothermic, the more stable radical is formed faster, and often a single radical halogenation product predominates.

38. Energetics of the Chlorination Rxn.
Calculating the H0 using bond dissociation energies for chlorination reveals that abstraction of a 10 or 20 hydrogen by Cl• is exothermic.
Since chlorination has an exothermic rate-determining step, the transition state to form both radicals resembles the same starting material, CH3CH2CH3. Thus, the relative stability of the two radicals is much less important, and both radicals are formed.

39. Transition State in the Chlorination of Propane
Conclusion: Because the rate-determining step in chlorination is exothermic, the transition state resembles the starting material, both radicals are formed, and a mixture of products results.

40. Radical Inhibitors

41. Radical Inhibitors
Compounds that prevent radical reactions from occurring are called radical inhibitors or radical scavengers. Besides O2, vitamin E and other related compounds are radical scavengers.
The reaction of a radical with oxygen (a diradical in its ground state electronic configuration) is an example of two radicals reacting with each other.

42. Antioxidants
An antioxidant is a compound that stops an oxidation from occurring.
Naturally occurring antioxidants such as vitamin E prevent radical reactions that can cause cell damage.
Synthetic antioxidants such as BHT—butylated hydroxy toluene—are added to packaged and prepared foods to prevent oxidation and spoilage.
Vitamin E and BHT are radical inhibitors, so they terminate radical chain mechanisms by reacting with the radical.

43. Resonance-Stabilized Radical
To trap free radicals, both vitamin E and BHT use a hydroxy group bonded to a benzene ring—a general structure called a phenol.
Radicals (R•) abstract a hydrogen atom from the OH group of an antioxidant, forming a new resonance-stabilized radical. This new radical does not participate in chain propagation, but rather terminates the chain and halts the oxidation process.
Because oxidative damage to lipids in cells is thought to play a role in the aging process, many anti-aging formulations contain antioxidants.

44. SN2 & SN1 Reacitons

45. Rate Equation
A rate law or rate equation shows the relationship between the reaction rate and the concentration of the reactants. It is experimentally determined.

46. Rate Constants Fast reactions have large rate constants.
Slow reactions have small rate constants.
The rate constant k and the energy of activation Ea are inversely related. A high Ea corresponds to a small k.
A rate equation contains concentration terms for all reactants in a one-step mechanism.
A rate equation contains concentration terms for only the reactants involved in the rate-determining step in a multi-step reaction.
The order of a rate equation equals the sum of the exponents of the concentration terms in the rate equation.

47. Reaction Kinetics The larger the Ea the slower the reaction.
The higher the concentration, the faster the rate. (increasing concentration increases number of collisions between reacting molecules)
The higher the temperature, the faster the rate. (increasing temp. increases the average kinetic energy of the reacting molecules-kinetic energy of molecules is used for bond cleavage) As a general rule, increasing the reaction temp. by 10°C doubles the reaction rate.
G0, H0, and Keq do not determine the rate of a reaction. These quantities indicate the direction of the equilibrium and the relative energy of reactants and products.

48. Rate Determining Step
A two-step reaction has a slow rate-determining step, and a fast step.
In a multi-step mechanism, the reaction can occur no faster than its rate-determining step.
Only the concentration of the reactants in the rate-determining step appear in the rate equation.

49. Stereochemistry of Halogenation

50. Radical Reactions
Stereochemistry of Halogenation

52. Radical Reactions Stereochemistry of Halogenation
Halogenation of an achiral starting material such as CH3CH2CH2CH3 forms two constitutional isomers by replacement of either a 10 or 20 hydrogen.
1-Chlorobutane has no stereogenic centers and is thus achiral.
2-Chlorobutane has a new stereogenic center, and so an equal amount of two enantiomers must form—a racemic mixture.

53. Radical Reactions Stereochemistry of Halogenation
A racemic mixture results because the first propagation step generates a planar sp2 hybridized radical. Cl2 then reacts with it from either side to form an equal amount of two enantiomers.

54. Radical Reactions Stereochemistry of Halogenation
Suppose we were to chlorinate the chiral starting material (R)-2-bromobutane at C2 and C3.
Chlorination at C2 occurs at the stereogenic center.
Radical halogenation reactions at a stereogenic center occur with racemization.

55. Radical Reactions Stereochemistry of Halogenation
Chlorination at C3 does not occur at the stereogenic center, but forms a new stereogenic center.
Since no bond is broken to the stereogenic center at C2, its configuration is retained during the reaction.
The trigonal planar sp2 hybridized radical is attacked from either side by Cl2, forming a new stereogenic center.
A pair of diastereomers is formed.

57. Allylic Halogenation Reaction

58. Allyl Carbon Radical
An allylic carbon is a carbon adjacent to a double bond.
Homolysis of the allylic C—H bond in propene generates an allylic radical which has an unpaired electron on the carbon adjacent to the double bond.
The bond dissociation energy for this process is even less than that for 30 C—H bond (91 kcal/mol).
This means that an allyl radical is more stable than a 30 radical.

59. Allylic Carbon Radical
The allyl radical is more stable than other radicals because two resonance forms can be drawn for it.

60. Autoxidation at the Allylic Carbon
Oils are susceptible to allylic free radical oxidation.

61. Radical Initiators
Radicals are formed from covalent bonds by adding energy in the form of heat () or light (h).
Some radical reactions are carried out in the presence of a radical initiator, which contain an especially weak bond that serves as a source of radicals.
Peroxides, compounds having the general structure RO—OR, are the most commonly used radical initiators.
Heating a peroxide readily causes homolysis of the weak O—O bond, forming two RO• radicals.

62. Allylic Bromination w/ NBS
Because allylic C—H bonds are weaker than other sp3 hybridized C—H bonds, the allylic carbon can be selectively halogenated using NBS in the presence of light or peroxides.
NBS contains a weak N—Br bond that is homolytically cleaved with light to generate a bromine radical, initiating an allylic halogenation reaction.
Propagation then consists of the usual two steps of radical halogenation.

63. NBS Promoted Allylic Bromination Reaction

64. Dual Roles for NBS
NBS also generates a low concentration of Br2 needed in the second chain propagation step (Step [3] of the mechanism).
The HBr formed in Step [2] reacts with NBS to form Br2, which is then used for halogenation in Step [3] of the mechanism.

66. Bromine Addition vs Allylic Brominations
Thus, an alkene with allylic C—H bonds undergoes two different reactions depending on the reaction conditions.

67. Understanding Product Outcome
Question:
Why does a low concentration of Br2 (from NBS) favor allylic substitution (over ionic addition to form the dibromide)?
Answer:
The key to getting substitution is to have a low concentration of bromine (Br2).
The Br2 produced from NBS is present in very low concentrations.
A low concentration of Br2 would first react with the double bond to form a low concentration of the bridged bromonium ion.
The bridged bromonium ion must then react with more bromine (in the form of Br¯) in a second step to form the dibromide.
If concentrations of both intermediates—the bromonium ion and Br¯ are low (as is the case here), the overall rate of addition is very slow, and the products of the very fast and facile radical chain reaction predominate.

68. Addition of Br for Allyl Radical
Halogenation at an allylic carbon often results in a mixture of products. Consider the following example:
A mixture results because the reaction proceeds by way of a resonance stabilized radical.

70. Addition of Radicals to Double bonds

71. Radical Additions to Double Bonds
HBr adds to alkenes to form alkyl bromides in the presence of heat, light, or peroxides.
The regioselectivity of the addition to unsymmetrical alkenes is different from that in addition of HBr in the absence of heat, light or peroxides.
The addition of HBr to alkenes in the presence of heat, light or peroxides proceeds via a radical mechanism.

73. Radical Additions to Double Bonds

74. Radical Additions to Double Bonds
Note that in the first propagation step, the addition of Br• to the double bond, there are two possible paths:
Path [A] forms the less stable 10 radical
Path [B] forms the more stable 20 radical
The more stable 20 radical forms faster, so Path [B] is preferred.

75. Radical Additions to Double Bonds
The radical mechanism illustrates why the regioselectivity of HBr addition is different depending on the reaction conditions.

76. Radical Additions to Double Bonds
HBr adds to alkenes under radical conditions, but HCl and HI do not. This can be explained by considering the energetics of the reactions using bond dissociation energies.
Both propagation steps for HBr addition are exothermic, so propagation is exothermic (energetically favorable) overall.
For addition of HCl or HI, one of the chain propagating steps is quite endothermic, and thus too difficult to be part of a repeating chain mechanism.