1. Alkene Addition Reaction
Practice prediction of major products
Attention to regioselectivity and stereochemistry
Attempt synthesis by using all addition reactions
Master mechanisms for
Halohydrogenation
Hydration (with possible Rearrangement)
Halogenation

2. Addition Reaction Addition is the opposite of elimination
A π bond is converted to a s bond

3. Addition Reaction as Lewis Acid/Base Rxn.
A pi bond will often act as a Lewis base (as a nucleophile or as a Brønsted-Lowry base). Cation as Lewis acid.

4. Addition / Elimination Equilibria
Because an addition is the reverse of an elimination, often the processes are at equilibrium
An equilibrium is dynamic process
The sign of ΔG (the free energy) dictates which side the equilibrium will favor

5. Energy/Entropy for Addition Rxn
Bonds broken – bonds formed = 166 kcal/mol – 185 kcal/mol = –19 kcal/mol
Typical addition reactions: ΔH < 0, ΔS < 0.

6. Low Temperature Favor Addition
Since
To favor addition, a –ΔG is needed
The entropy term needs to be small (including negative) to favor addition.
Since –TΔS is always positive, lower Temperature would help addition
Conversely, high temperature favors elimination.

7. I. Hydrohalogenation (+ HX)
Note the low temperature used in this addition reaction
Symmetrical alkene gives single addition product unless rearrangement occurs
For asymmetrical alkenes, multiple products may arise yet addition rxn may show preference (selectivity, regiochemistry)

8. Selectivity in Hydrohalogenation
When HX added to Asymmetrical alkene:
Markovnikov (1869) showed that in general, H atoms tend to add to the carbon already bearing more H atoms

9. Markovnikov’s rule for Hydrohalogenation
Or, in general, halogen atoms tend to add to the carbon that is more substituted with other carbon groups
Regioselective reaction: One constitutional isomer is formed in greater quantity than another
The structure of the minor product for the above?

10. Mechanism for Addition Reaction
The rate law of Markovnikov rxn : rate = k[alkene][HX]
Thus a two step mechanism:
Protonation of C=C bond by HX, followed by nucleophilic attack by halide

11. Carbocation as rxn intermediate

12. Hydrohalogenation via Carbocation
The stability of carbocation dictate the Markovnikov regioselectivity

13. Stable carbocation has lower activation energy

14. Addition Products as Racemic Mixture
Although chirality centers are formed, addition of halide on carbocation gives racemic mixture (equal mix)
Carbocation (sp2) allows addition from both sides

15. Rearrangements on Carbocation
Rearrangements (hydride or methyl shifts) occur for the carbocation if the shift makes it more stable. Mechanism:

16. Rearrangement gives more product
Significant diversity of products limits synthetic utility 

17. Regioselectivity depends on Reagents/Solvent/Catalyst used!
Anti-Markovnikov addition: Addition in the presence of peroxides such as H2O2
The different regioselectivities are the result of different Reaction mechanism.

18. Predict Addition Product and Mechanism
Predict the major product(s) and Mechanism for B

19. II: Acid Catalyzed Hydration
The components of water (-H and –OH) are added across a C=C double bond
The acid catalyst is often shown over the arrow, because it is regenerated rather than being a reactant

20. Rate of Hydration Rxn
Acid catalyzed hydration shows preference of more substituted alkene

21. Hydration Mechanism: Carbocation

22. Hydration Thermodynamics
Similar to Hydrohalogenation, hydration reactions are also reversible
Exothermic, entropy decrease process
Thus low temperature could help Hydration
Addition
Elimination

23. Hydration Elimination Equilibrium
Note the concentrated sulfuric acid strongly absorbs/removes water from reaction to help elimination (Châtelier’s principle)

24. Hydration: Stereochemistry
Similar to Hydrohalogenation, the stereochemistry of hydration reactions is controlled by the geometry of the carbocation, yielding a racemic mixture

25. Application of Hydration
Industrial production of ethanol utilizes hydration reaction of ethylene (ethene)
In general, the presence of carbocation intermediate allows rearrangement, thus only limited application for synthesis 

26. III: Oxymercuration-Demercuration
In carbocation mechanism, rearrangements often produce a mixture of products, the synthetic utility of Markovnikov hydration reactions is somewhat limited
Oxymercuration-demercuration is an alternative process to synthesize alcohol (Markovnikov products) without the possibility of rearrangement

27. Mercuric cation (HgOAc+)
Oxymercuration begins with mercuric acetate
Mercuric cation
As an electrophile (positive charge)
As a Lewis acid
Alkene is a nucleophile

28. Mercuration & Nucleophilic Attack
Nucleophile water attacks the carbon with more substituents (eventually leading to Markovnikov alcohol)

29. Demercuration
NaBH4 is generally used to replace the –HgOAc group with a –H group via a free radical mechanism.

30. IV. Hydroboration-Oxidation
To achieve anti-Markovnikov hydration, Hydroboration-Oxidation is often used
THF for tetrahydrofuran, an ether
Note that the process occurs in two steps

31. Hydroboration-Oxidation: Syn Addition
Hydroboration-Oxidation reactions achieve syn addition
Anti addition is NOT observed

32. BH3 , B2H6, BH3•THF BH3 : similar to a carbocation, electrophile
Dimerization of borane forms more stable diborane (B2H6). BH3•THF is stabilized, used as hydroboration agent

33. Hydroboration: Addition of Borane
C=C as nucleophile/Lewis base attacks borane
Two more cycles gives R3B.
Boron attacks Carbon with fewer substituents.

34. Oxidation with H2O2 forms alcohol

35. Hydroboration forming One chiral center
When ONE chirality center is formed, a racemic mixture results, similar to carbocation addition.
Borane can add to alkene from both sides of the C=C bond, leading to both R and S products.
Anti-Markovnikov alcohol

36. Stereochemistry involving TWO chiral centers
SYN addition of B-H bond on C=C bond:
When TWO chirality centers are formed, a racemic mixture results. The syn addition of H and OH.
Two stereoisomers: (3S, 4R) and (3R, 4S) only, No (3S, 4S) nor (3R, 4R) products formed.
Concerted addition of B-H bond!

37. Predict Hydration Product

38. III. Catalytic Hydrogenation
The addition of H2 across a C=C double bond
Stereochemistry: If a chirality center is formed, syn addition is observed

39. Catalytic Hydrogenation: Energy diagram
Without catalyst: Exothermic reaction with high activation energy
Typical catalysts include Pt, Pd, and Ni

40. Catalytic Hydrogenation: Mechanism
The metal catalyst is believed to both adsorb the H atoms and coordinate the alkene
The H atoms add to the same side of the alkene pi system

41. IV. Halogenation: Add X-X
Halogenation involves adding two halogen atoms across a C=C double bond
Halogenation is a key step in the production of PVC

42. Halogenation: Energetics and Stereochemistry
Exothermic: Halogenation with Cl2 and Br2 is generally effective, but halogenation with I2 is too slow and halogenation with F2 is too violent
Halogenation occurs with anti addition

43. Polarizibility of X2 Allows Nuc: Attack
Halogen molecules (Br2. Cl2 ) is nonpolar, but polarizable (Br+ -Br-)
Nucleophile (such as alkene) attacks positive charge of Br2
During nucleophilic attack, bromide ion as leaving group

44. Halogenation: No Carbocation intermediate
If alkene attacking Br2 , forming a carbocation in a similar way as protonation, carbocation intermediate would allow nucleophilic attack from both sides
Such mechanism DOES NOT match the stereospecificity of the reaction.

45. Bromination via Bromonium ion
The intermediate brominium ion was detected by NMR spectroscopy in 1967 ( )

46. Anti addition for Halogenation
Only anti addition is observed
Can you design a synthesis for ?

47. Predict the major halogenation product

48. V. Halohydrin from HOX addition
Alkene reacts with Cl2 or Br2 in water, forming halohydrin
Regioselectivity: The –OH group adds to the more substituted carbon
Stereochemistry: Anti addition

49. Halohydration Mechanism
1st step: Reaction with halogen to form bromonium ion
2nd step: water as nucleophile attack on backside. Due to the excess water (solvent)
Finally, deprotonation

50. Halohydrin Regioselectivity
Water attacks the bromonium from one side that goes through the lower energy transition state: remember the stability of carbocation affects transition state.
Steric effect is negligible due to small size of water
Transition state

51. -halogenated Ether from X2 in Alcohol
Alkene reacts with Cl2 or Br2 in alcohol (ROH), forming -halogenated ether
Regioselectivity and Stereochemistry: The –OR group adds to the more substituted carbon, with anti addition

52. Practice: Halohydrin formation
Predict the major product(s) or Find the reagents

53. VI. Anti Dihydroxylation
Dihydroxylation (addition of TWO hydroxyl groups) occurs when two –OH groups are added across a C=C double bond
Anti dihydroxylation involves peroxy acid (RCO3H) /acid hydrolysis:

54. Formation of Epoxide First, an epoxide is formed
Alkene as nucleophile attacking electron deficient O-O bond, thermodynamic driven
Epoxide is unstable
Meta-chloroperbenzoic acid (MCPBA)

55. Activation and Attacking of Epoxide
epoxide is activated/protonated with an acid
Water as nucleophile attack backside
Deprotonation

56. Protonated Epoxide Allows for Anti addition
Note the similarities between three key intermediates
Ring strain and a +1 formal charge makes these structures GREAT electrophiles
Each yield anti products, because the nucleophile must attack from the side opposite the leaving group

57. VII. Syn Dihydroxylation
Like other syn additions, syn dihydroxylation adds across the C=C double bond in ONE step

58. OsO4 for Syn Dihydroxylation
Because OsO4 is expensive and toxic, conditions have been developed where the OsO4 is regenerated after reacting, so only catalytic amounts are needed

59. MnO4- in Syn Dihydroxylation
MnO4- is similar to OsO4 but more reactive
Syn dihydroxylation can be achieved with KMnO4 but only under mild conditions (cold temperatures)
Diols are often further oxidized by MnO4-, and MnO4- is reactive toward many other functional groups as well
The synthetic utility of MnO4- is limited

60. Synthetic idea for Dihydroxylation
Choose the proper reagent for the transformation below

61. Oxidative Cleavage with O3
C=C double bonds are also reactive toward oxidative cleavage: >C=C< + O3  >C=O + O=C<
Ozonolysis is one such process

62. Ozonolysis Mechanism
Common reducing agents: dimethyl sulfide (DMS) and Zn/H2O.

63. Practice: Oxidative Cleavage with O3
Predict the major product(s) for the reaction below

64. ***Predicting Addition Products
Analyze the reagents used to determine what groups will be added across the C=C double bond
Determine the regioselectivity (Markovnikov or anti-Markovnikov)
Determine the stereospecificity (syn or anti addition)
Memorization required: Reagent/Solvent; Mechanistic rationale (the intermediate)
The more familiar you are with the mechanisms (through practice), the easier predicting products will be

65. ***Organize your notes
Substrate
Reagent/solvent, steps involved
Key Rxn Intermediate
Main product(s)
Regioselectivity, Stereoselectivity
RCO3H
H3O+
Anti

66. ***One Step Syntheses
To set up a synthesis, assess the reactants and products to see what changes need to be made
Label each of the processes below

67. One Step Syntheses
To set up a synthesis, assess the reactants and products to see what changes need to be made
Give reagents and conditions for the following
Practice with SkillBuilder 9.10

68. Additional Practice Problems
If you want to favor addition rather than elimination, do you generally want a high or low temperature, and why?

69. Additional Practice Problems
Predict the major product for the addition reaction below. Be aware of possible rearrangements and stereochemical concerns.

70. Additional Practice Problems
How and why will the concentration of acid affect whether an acid catalyzed hydration will favor products or reactants at equilibrium?

71. Additional Practice Problems
Give an example reaction for Markovnikov hydration without the possibility of rearrangement.
Give an example reaction for syn antiMarkovnikov hydration.

72. Additional Practice Problems
Should a halogenation reaction be overall first or second order kinetics? Also, Explain why it gives anti addition rather than syn.

73. Additional Practice Problems
What reagents are necessary to achieve the following synthesis?

74. Predict the major product of Hydroboration-Oxidation
major product(s) for the reactions below

75. Homogeneous catalyst for Catalytic Hydrogenation
If catalysis takes place on the surface of a solid surrounded by solution, the catalyst is heterogeneous.
Homogeneous catalysts (Wilkinson et al, 1966; 1973 Nobel) have been developed:

76. Asymmetric Hydrogenation
In 1968, Knowles (2001 Nobel) modified Wilkinson’s catalyst by using a chiral phosphine ligand
A chiral catalyst can produce one desired enantiomer over another. Particularly important for bio/medicinal related purpose, such as drug or insecticide.

77. Energy diagram for asymmetric hydrogenation
A chiral catalyst allows one enantiomer to be formed more frequently in the reaction mixture
Kinetically favored or thermodynamically favored?
Some chiral catalysts give better enantioselectivity than others. WHY?

78. Asymmetric Catalysis: A “Hot” Field
BINAP is a chiral ligand that gives pronounced enantioselectivity
For any reaction, stereoselectivity can only be achieved if at least one reagent (reactant or catalyst) is chiral

79. Mechanism for Addition Reaction
The rate law of Markovnikov rxn : rate = k[alkene][HX]
Thus a two step mechanism:
Protonation of C=C bond by HX (slow) gives carbocation
Addition of X- to carbocation (fast) gives alkyl halide

80. Rearrangements on Carbocation
Rearrangements (hydride or methyl shifts) occur for the carbocation if the shift makes it more stable

81. Hydration Mechanism: Carbocation
Similar to Markovnikov Hydrohalogenation

82. Mechanism for Addition Reaction
The rate law of Markovnikov rxn : rate = k[alkene][HX]
Thus a two step mechanism:
Protonation of C=C bond by HX, followed by nucleophilic attack by halide

83. Mechanism: Bromonium ion
bromine atom shares lone pair electrons with carbocation  bromonium ion
The intermediate brominium ion was detected by NMR spectroscopy in 1967 ( )

84. Backside Bromide attack on Bromonium

85. Halohydration Mechanism
1st step: Reaction with halogen to form bromonium ion
2nd step: water as nucleophile attack on backside. Due to the excess water (solvent)
Finally, deprotonation

86. Practice: Asymmetric Hydrogenation
Predict the major product(s) for the reactions below

87. Practice: stereochemistry in halogenation
Predict the major product(s) for the reactions below

88. Practice: Halohydrin Regioselectivity
Predict the major product(s) for the reactions below

89. Practice: Predict Addition Products
Predict the major product(s) for the reaction below

90. Practice: Oxidative Cleavage with O3
Predict the major product(s) for the reaction below
Treasure Hunt (2 extra credits due next class meeting): Find all the bicyclic reactants might give the product below