1. 6. An Overview of Organic Reactions
Why this chapter?
To understand organic and/or biochemistry, it is necessary to know:
-What occurs
-Why and how chemical reactions take place
We will see how a reaction can be described

2. 6.1 Kinds of Organic Reactions
In general, we look at what occurs and try to learn how it happens
Common patterns describe the changes
Addition reactions – two molecules combine
Elimination reactions – one molecule splits into two

3. Substitution – parts from two molecules exchange
Rearrangement reactions – a molecule undergoes changes in the way its atoms are connected

4. What kind of reaction is the transformation shown below?
Learning Check:
What kind of reaction is the transformation shown below?
an elimination reaction
a rearrangement reaction
a substitution reaction
an addition reaction
none of these

5. What kind of reaction is the transformation shown below?
Solution:
What kind of reaction is the transformation shown below?
an elimination reaction
a rearrangement reaction
a substitution reaction
an addition reaction
none of these

6. 6.2 How Organic Reactions Occur: Mechanisms
In a clock the hands move but the mechanism behind the face is what causes the movement
In an organic reaction, we see the transformation that has occurred. The mechanism describes the steps behind the changes that we can observe
Reactions occur in defined steps that lead from reactant to product

7. Steps in Mechanisms We classify the types of steps in a sequence
A step involves either the formation or breaking of a covalent bond
Steps can occur in individually or in combination with other steps
When several steps occur at the same time they are said to be concerted

8. Types of Steps in Reaction Mechanisms
Bond formation or breakage can be symmetrical or unsymetrical
Symmetrical- homolytic
Unsymmetrical- heterolytic
Bond Breaking
Bond Making

9. Indicating Steps in Mechanisms
Curved arrows indicate breaking and forming of bonds
Arrowheads with a “half” head (“fish- hook”) indicate homolytic and homogenic steps (called ‘radical processes’)
Arrowheads with a complete head indicate heterolytic and heterogenic steps (called ‘polar processes’)

10. 6.3 Radical Reactions Not as common as polar reactions
Radicals react to complete electron octet of valence shell
A radical can break a bond in another molecule and abstract a partner with an electron, giving substitution in the original molecule
A radical can add to an alkene to give a new radical, causing an addition reaction

11. Steps in Radical Substitution
Three types of steps
Initiation – homolytic formation of two reactive species with unpaired electrons
Example – formation of Cl atoms form Cl2 and light
Propagation – reaction with molecule to generate radical
Example - reaction of chlorine atom with methane to give HCl and CH3.
Termination – combination of two radicals to form a stable product: CH3. + CH3.  CH3CH3

12. Steps in Radical Substitution: Monochlorination of Methane
Initiation
Propagation

13. Steps in Radical Substitution
Termination
With excess concentration of Cl2 present continued reaction is probable with formation of dichloro, trichloro, and tetrachloro methanes.

14. Radical Substitution Example:
Biosynthesis of Prostaglandins
p. 141

15. Radical Example:
p. 142

16. Learning Check:
Propose a mechanism. Add curved arrows to indicate the flow of electrons:
p. 142

17. Solution:
Propose a mechanism. Add curved arrows to indicate the flow of electrons:
p. 142

18. Learning Check:
In a radical chain reaction, what would be the best description of the following reaction? H3C• •Cl → CH3Cl
propagation
elimination
initiation
termination
substitution

19. Solution:
In a radical chain reaction, what would be the best description of the following reaction? H3C• •Cl → CH3Cl
propagation
elimination
initiation
termination
substitution

20. Radical Substitution: With >1 kind of H
When there is
>1 type of H then there is
>1 option for radical formation and therefore
>1 option for a monohalogenation product.

21. Learning Check:
In the reaction of Cl2 with 2-methylbutane, how many monochlorinated isomers are produced? 2 3 4 5 6

22. Solution:
In the reaction of Cl2 with 2-methylbutane, how many monochlorinated isomers are produced? 2 3 4 5 6

23. 6.4 Polar Reactions
Molecules can contain local unsymmetrical electron distributions due to differences in electronegativities
This causes a partial negative charge on an atom and a compensating partial positive charge on an adjacent atom
The more electronegative atom has the greater electron density
Elements such as O, F, N, Cl more electronegative than carbon

24. p. 143

26. Polarizability
Polarization is a change in electron distribution as a response to change in electronic nature of the surroundings
Polarizability is the tendency to undergo polarization
Polar reactions occur between regions of high electron density and regions of low electron density

27. Polarizability
Bonds inherently polar already can be made more polar by reactions with acids or bases.
p. 144

28. Polarizability
Bonds not inherently polar can be polarizable as interactions with solvent or other polar molecules effect the electron distribution.
2.55
2.58
2.66
Large atoms with loosely held electrons are more polarizable than small atoms with few tightly held electrons.
So: S is more polarizable than O
I is more polarizable than Cl
p. 144

29. Generalized Polar Reactions
An electrophile, an electron-poor species, combines with a nucleophile, an electron-rich species
An electrophile is a Lewis acid
A nucleophile is a Lewis base
The combination is indicate with a curved arrow from nucleophile to electrophile

30. Figure 5. 1: Some nucleophiles and electrophiles
Figure 5.1: Some nucleophiles and electrophiles. Electrostatic potential maps identify the nucleophilic (red; negative) and electrophilic (blue; positive) atoms.
Fig. 5-1a, p. 145

31. Learning Check:
Which of the following is likely to be a nucleophile and which an electrophile?
p. 146

32. Solution:
Which of the following is likely to be a nucleophile and which an electrophile? E E N N
p. 146

33. Learning Check:
Is BF3 is likely to be a nucleophile or an electrophile?
p. 146

34. Solution: E Is BF3 is likely to be a nucleophile or an electrophile?

35. Which of the following is expected to be the worst nucleophile?
Learning Check:
Which of the following is expected to be the worst nucleophile?
NH3
H2O
BH3
ethylene
(CH3) 3P

36. Which of the following is expected to be the worst nucleophile?
Solution:
Which of the following is expected to be the worst nucleophile?
NH3
H2O
BH3
ethylene
(CH3) 3P

37. 6.5 An Example of a Polar Reaction: Addition of HBr to Ethylene
HBr adds to the  part of C-C double bond
The  bond is e- rich, allowing it to function as a nucleophile
H-Br is electron deficient at the H since Br is much more electronegative, making HBr an electrophile

38. Mechanism of Addition of HBr to Ethylene
HBr electrophile is attacked by  electrons of ethylene (nucleophile) to form a carbocation intermediate and bromide ion
Bromide adds to the positive center of the carbocation, which is an electrophile, forming a C-Br  bond
The result is that ethylene and HBr combine to form bromoethane
All polar reactions occur by combination of an electron- rich site of a nucleophile and an electron-deficient site of an electrophile

39. Figure 5. 2: A comparison of carbon–carbon single and double bonds
Figure 5.2: A comparison of carbon–carbon single and double bonds. A double bond is both more accessible to approaching reactants than a single bond and more electron-rich (more nucleophilic). An electrostatic potential map of ethylene indicates that the double bond is the region of highest negative charge (red).
Fig. 5-2a, p. 148

40. Learning Check:
What product would you expect?
p. 142

41. Solution:
What product would you expect?
p. 142

42. 6.6 Using Curved Arrows in Polar Reaction Mechanisms
Curved arrows are a way to keep track of changes in bonding in polar reaction
The arrows track “electron movement”
Electrons always move in pairs
Charges change during the reaction
One curved arrow corresponds to one step in a reaction mechanism

43. Rules for Using Curved Arrows
The arrow (electrons) goes from the nucleophilic reaction site (Nu: or Nu:- ) to the electrophilic reaction site (sink, E or E+)
The nucleophilic site can be neutral or negative

44. Rules for Using Curved Arrows
The nucleophilic site can be negative or neutral

45. The electrophilic site can be positive or neutral

46. The octet rule must be followed
The hydrogen already has two e-s so when another pair moves in the 2 already owned have to leave.

47. What is the role of the alkene in the reaction above?
Learning Check:
What is the role of the alkene in the reaction above?
electrophile
nucleophile
free radical
catalyst
Lewis acid

48. What is the role of the alkene in the reaction above?
Solution:
What is the role of the alkene in the reaction above?
electrophile
nucleophile
free radical
catalyst
Lewis acid

49. Learning Check: Add curved arrows to indicate the flow of electrons:
p. 151

50. Solution:
Add curved arrows to indicate the flow of electrons:
p. 151

51. Learning Check: Add curved arrows to indicate the flow of electrons:
p. 152

52. Solution:
Add curved arrows to indicate the flow of electrons:

53. Learning Check:
Predict the products of the following reaction:
p. 152

54. Solution:
Predict the products of the following reaction:
p. 152

55. Learning Check:
Which of the following represents a correctly drawn reaction mechanism? x

56. Solution:
Which of the following represents a correctly drawn reaction mechanism? x

57. Learning Check:
What carbocation intermediate is consistent with the product formed? Propose a mechanism. (Add curved arrows to indicate the flow of electrons.)
p. 142

58. Solution:
What carbocation intermediate is consistent with the product formed? Propose a mechanism. (Add curved arrows to indicate the flow of electrons.)
Not formed
p. 142

59. 6.7 Describing a Reaction: Equilibria, Rates, and Energy Changes
Reactions can go either forward or backward to reach equilibrium
The multiplied concentrations of the products divided by the multiplied concentrations of the reactant is the equilibrium constant, Keq
Each concentration is raised to the power of its coefficient in the balanced equation.

60. p. 153

61. Magnitudes of Equilibrium Constants
If the value of Keq >1, this indicates that at equilibrium most material is present as products
If Keq = 10, then the concentration of the product is ten times that of the reactant
A value of Keq < 1 indicates that at equilibrium most material is present as the reactant
If Keq = 0.10, then the concentration of the reactant is ten times that of the product

62. Free Energy and Equilibrium
The ratio of products to reactants is controlled by their relative Gibbs free energy
This energy is released on the favored side of an equilibrium reaction
The change in Gibbs free energy between products and reacts is written as “DG”
If Keq > 1, energy is released to the surroundings (exergonic reaction)
If Keq < 1, energy is absorbed from the surroundings (endergonic reaction)

63. Numeric Relationship of Keq and Free Energy Change
The standard free energy change at 1 atm pressure and 298 K is DGº
The relationship between free energy change and an equilibrium constant is:
DGº = - RT ln Keq where
R = cal/(K x mol)
T = temperature in Kelvin
ln Keq = natural logarithm of Keq

64. This reaction is exothermic
ΔHo is the heat, or enthalpy, of reaction.
ΔHo < 0 ; The reaction is exothermic. ΔHo > 0 ; The reaction is endothermic.
ΔG, the Gibbs free energy change, determines Keq and whether the reaction is spontaneous or nonspontaneous.
ΔGo < 0 ; The reaction is spontaneous. ΔGo > 0 ; The reaction is nonspontaneous. ΔGo < 0 ; Keq > 1 ΔGo = 0 ; Keq = 1 ΔGo > 0 ; Keq < 1
This reaction is exothermic
This reaction is spontaneous
The equilibrium lies toward product
p. 154

65. 6.2

66. Which of the following equations is correct?
Learning Check:
Which of the following equations is correct?
∆G = ∆H – T∆S
∆G = ∆s + T∆H
∆H = T∆G – T∆S
∆G = ∆H + T∆S
∆S = T∆H – ∆G

67. Which of the following equations is correct?
Solution:
Which of the following equations is correct?
∆G = ∆H – T∆S
∆G = ∆s + T∆H
∆H = T∆G – T∆S
∆G = ∆H + T∆S
∆S = T∆H – ∆G

68. 6.8 Describing a Reaction: Bond Dissociation Energies
Bond dissociation energy (D): amount of energy required to break a given bond to produce two radical fragments when the molecule is in the gas phase at 25˚ C
The energy is mostly determined by the type of bond, independent of the molecule
The C-H bond in methane requires a net heat input of 105 kcal/mol (438 kJ/mol) to be broken at 25 ºC.
Table 5.3 lists energies for many bond types
Changes in bonds can be used to calculate net changes in heat

69. Bond Dissociation Energies
Table 5-3a, p. 156

70. Bond Dissociation Energies
Table 5-3b, p. 156

71. Bond Dissociation Energies
Calculate the DHo for the chlorination of methane : Cl CH → CH3Cl HCl
bond
CH3–H
CH3–Cl
H–Cl
H–H
Cl–Cl
BDE (kJ/mol)
438
351
432
436
243
Bonds Broken
Bonds Made
Cl-Cl kJ/mol
H3C-Cl kJ/mol
H-Cl kJ/mol
H3C-H kJ/mol
+681 kJ/mol
-783 kJ/mol
DHo = = -102 kJ/mol
p. 157

72. p. 157

73. Consider the following reaction: CH3I + H2O → CH3OH + HI
Learning Check:
Consider the following reaction: CH3I + H2O → CH3OH + HI
If BDEs are used to estimate the enthalpy of this reaction, which bond’s BDE is not needed?
CH3–I
HO–H
H–I
CH3O–H
CH3–OH

74. Consider the following reaction: CH3I + H2O → CH3OH + HI
Solution:
Consider the following reaction: CH3I + H2O → CH3OH + HI
If BDEs are used to estimate the enthalpy of this reaction, which bond’s BDE is not needed?
CH3–I
HO–H
H–I
CH3O–H
CH3–OH

75. Learning Check: What is the reason that this step is not observed?
The BDE’s for some bonds are collected in the table below: An alternative step in chlorination of methane might be as follows: Cl• CH → CH3Cl H•
bond
CH3–H
CH3–Cl
H–Cl
H–H
Cl–Cl
BDE (kJ/mol)
438
351
432
436
243
What is the reason that this step is not observed?
Cl• cannot approach the carbon atom close enough to form a bond because of steric interference from hydrogens
H• is not among the products of methane chlorination
Cl• can only bond to hydrogen atoms
this step is too endothermic as compared to alternatives
this step is too exothermic

76. Solution: What is the reason that this step is not observed?
The BDE’s for some bonds are collected in the table below: An alternative step in chlorination of methane might be as follows: Cl• CH → CH3Cl H•
bond
CH3–H
CH3–Cl
H–Cl
H–H
Cl–Cl
BDE (kJ/mol)
438
351
432
436
243
What is the reason that this step is not observed?
Cl• cannot approach the carbon atom close enough to form a bond because of steric interference from hydrogens
H• is not among the products of methane chlorination
Cl• can only bond to hydrogen atoms
this step is too endothermic as compared to alternatives
this step is too exothermic

77. The following reaction is an example of: H3C+ + Cl– → CH3Cl
Solution:
The following reaction is an example of: H3C Cl– → CH3Cl
a termination step
a heterolytic process
an initiation step
a homogenic process
an exergonic reaction

78. 6.9 Describing a Reaction: Energy Diagrams and Transition States
The highest energy point in a reaction step is called the transition state
The energy needed to go from reactant to transition state is the activation energy (DG‡)

79. First Step in Addition
In the addition of HBr the (conceptual) transition-state structure for the first step
The  bond between carbons begins to break
The C–H bond begins to form
The H–Br bond begins to break

80. Slow exergonic Fast exergonic Slow endergonic Fast endergonic
Figure 5.6: Some hypothetical energy diagrams.
(a) A fast exergonic reaction (small ΔG‡, negative ΔG°).
Fig. 5-6a, p. 159

81. Learning Check: I II III IV V
Which part of the following energy diagram indicates whether the overall reaction is exergonic or endergonic? I II
III IV V

82. Solution:
Which part of the following energy diagram indicates whether the overall reaction is exergonic or endergonic? I II
III IV V

83. Which statement about free energy is correct?
Learning Check:
Which statement about free energy is correct?
The ∆G of a reaction depends on the reaction mechanism (path).
The ∆G‡ of a reaction depends on the mechanism (path).
The ∆G of a reaction may be changed by adding a catalyst.
The bigger the ∆G value, the faster the reaction.
For exergonic reactions ∆G >0.

84. Which statement about free energy is correct?
Solution:
Which statement about free energy is correct?
The ∆G of a reaction depends on the reaction mechanism (path).
The ∆G‡ of a reaction depends on the mechanism (path).
The ∆G of a reaction may be changed by adding a catalyst.
The bigger the ∆G value, the faster the reaction.
For exergonic reactions ∆G >0.

85. 6.10 Describing a Reaction: Intermediates
If a reaction occurs in >1step, it must involve species that are neither the reactant nor the final product
These are called reaction intermediates or simply “intermediates”
Each step has its own free energy of activation
The complete diagram for the reaction shows the free energy changes associated with an intermediate

86. Figure 5.7: An energy diagram for the overall reaction of ethylene with HBr. Two separate steps are involved, each with its own transition state. The energy minimum between the two steps represents the carbocation reaction intermediate.

87. Learning Check: I II III IV V
On the reaction energy profile shown below, which of the species is the highest energy intermediate? I II
III IV V

88. Solution:
On the reaction energy profile shown below, which of the species is the highest energy intermediate? I II
III IV V

89. Which of the following statements is true?
Learning Check:
Which of the following statements is true?
Transition states can be observed and sometimes isolated.
Transition states can not be observed and never isolated.
Intermediates can be observed and sometimes isolated.
Intermediates can be observed but never isolated.
Intermediates can never be observed.

90. Which of the following statements is true?
Solution:
Which of the following statements is true?
Transition states can be observed and sometimes isolated.
Transition states can not be observed and never isolated.
Intermediates can be observed and sometimes isolated.
Intermediates can be observed but never isolated.
Intermediates can never be observed.

91. Learning Check:
Consider the reaction profile shown below. If there is a sufficient amount of thermal energy available to overcome the highest activation energy and sufficient time for all molecules to do that multiple times, what is the main structure present under such conditions? A B C D E

92. Solution:
Consider the reaction profile shown below. If there is a sufficient amount of thermal energy available to overcome the highest activation energy and sufficient time for all molecules to do that multiple times, what is the main structure present under such conditions? A B C D E

93. Learning Check:
Which energy difference corresponds to the activation energy of the rate-limiting step for A to E transformation?
B – A
C – A
D – A
E – A
D – C

94. Solution:
Which energy difference corresponds to the activation energy of the rate-limiting step for A to E transformation?
B – A
C – A
D – A
E – A
D – C

95. Which of the following statements is incorrect?
Learning Check:
Which of the following statements is incorrect?
Polar reactions must have ionic intermediates.
Initiation in radical-chain reactions must generate species with unpaired electrons.
Polar reactions occur between electrophiles and nucleophiles.
Lewis bases generally behave as nucleophiles.
Electrophiles can be neutral as well as positively charged.

96. Which of the following statements is incorrect?
Solution:
Which of the following statements is incorrect?
Polar reactions must have ionic intermediates.
Initiation in radical-chain reactions must generate species with unpaired electrons.
Polar reactions occur between electrophiles and nucleophiles.
Lewis bases generally behave as nucleophiles.
Electrophiles can be neutral as well as positively charged.

97. 6.11 A Comparison between Biological Reactions and Laboratory Reactions
Laboratory reactions usually carried out in organic solvent
Biological reactions in aqueous medium inside cells
They are promoted by catalysts that lower the activation barrier
The catalysts are usually proteins, called enzymes
Enzymes provide an alternative mechanism that is compatible with the conditions of life

98. Figure 5.8: An energy diagram for a typical, enzyme-catalyzed biological reaction (blue curve) versus an uncatalyzed laboratory reaction (red curve). The biological reaction involves many steps, each of which has a relatively small activation energy and small energy change. The end result is the same, however.
Fig. 5-8, p. 161

99. Figure 5.9: Models of hexokinase in space-filling and wireframe formats, showing the cleft that contains the active site where substrate binding and reaction catalysis occur. At the bottom is an X-ray crystal structure of the enzyme active site, showing the positions of both glucose and ADP as well as a lysine amino acid that acts as a base to deprotonate glucose.

100. 6.4
Table 5-4, p. 164

101. Learning Check:
Which of the following does not describe the role that can be played by an enzyme in a biological reaction?
It changes the mechanism of the reaction.
It lowers the energy of a transition state.
It changes the free-energy of the reaction.
It changes the rate of the reaction.
It increases the specificity of the reaction.

102. Solution:
Which of the following does not describe the role that can be played by an enzyme in a biological reaction?
It changes the mechanism of the reaction.
It lowers the energy of a transition state.
It changes the free-energy of the reaction.
It changes the rate of the reaction.
It increases the specificity of the reaction.