1. Reactivity and Mechanism
Thermochemistry Review: Enthalpy, Entropy, Free energy
Reaction Energy Diagram
Nucleophile and Electrophile
Mechanism and Arrow pushing

2. Energy Factors in Chemical Reaction
Chemical reactions are driven by both energy and entropy.
Enthalpy change (ΔH or q): the heat energy exchange between the reaction and its surroundings at constant pressure
Calculation:
ΔH = ∑ΔHf(product)- ∑ΔHf(reactant)
Estimation from bond energy:
ΔH ≈ ∑BE(reactant)- ∑BE(product)
For exothermic reaction, ΔH < 0; endothermic reaction, ΔH > 0

3. Enthalpy
Enthalpy change (ΔH or q): the heat energy exchange between the reaction and its surroundings at constant pressure
Calculation:
ΔH = ∑ΔHf(product)- ∑ΔHf(reactant)
Estimation from bond energy:
ΔH ≈ ∑BE(reactant)- ∑BE(product)
For exothermic reaction, ΔH < 0; endothermic reaction, ΔH > 0

4. Bond Dissociation Energy
Bonds can break homolytically or heterolytically (ΔH > 0)
Bond dissociation energy (BDE) or ΔH for bond breaking generally represents the energy associated with HOMOlytic cleavage

5. Bond Dissociation Energies
High BDE for stronger bond

6. Endothermic vs. Exothermic?
H• and F• free radicals come together to form bonds
A C–Br bond is broken
A strong bond is broken and a weak bond is formed
BE(reactant) > BE(product)
4. A weak bond is broken and a strong bond is formed
BE(reactant) < BE(product)
1,4: exothermic; 2,3: endothermic

7. Potential Energy Diagram
Qualitative description of Energy Change during reaction
Exothermic: energy of product lower than of reactant
Endothermic: energy of product higher than of reactant

8. Entropy change (ΔS)
Enthalphy and entropy (S) must BOTH be considered when predicting whether a reaction will occur
ΔG = ΔH – TΔS < 0
ENTROPY (S) : as molecular disorder, randomness, or freedom.
Total entropy is the combination of entropy of system and entropy of surroundings

9. Entropy and Reaction
The second law of Thermodynamics: the entropy of universe (aka total entropy) will increase for spontaneous change.
If ΔStot is positive, the forward process is spontaneous; ΔStot is negative, the reverse process is spontaneous
For chemical reactions, we must consider the entropy change for both the system (the reaction) and the surroundings (the solvent usually)

10. System Entropy Change (ΔSsys)
System entropy increases when
Reaction produces more molecules, especially gas product
The linkage within the molecule breaks
As such changes increases the number of possible translational, rotational, and/or vibrational distributions for the molecules

11. Entropy Change in Organic Chemical Reactions
Reaction A: entropy increase; B and C: entropy decrease

12. Surrounding entropy change ΔSsurr
Surrounding entropy change depends on reaction enthalpy change ΔHrxn :
ΔSsurr = - ΔHrxn/T
The more positive ΔSsurr The more product favored
Thus the more exothermic reaction (negative ΔHrxn), the reaction is more product favored

13. Gibbs Free Energy ΔG
Gibbs Free energy combines the effect of reaction enthalpy (ΔHsys) and system entropy (ΔSsys): ΔG < 0
A reaction
will always be spontaneous if exothermic and ΔSsys> 0
will never be spontaneous if endothermic and ΔSsys < 0
will be spontaneous only at high temperature if endothermic and ΔSsys > 0
will be spontaneous only at low temperature if exothermic and ΔSsys < 0

14. ΔG in action Consider the example reaction
ΔSsys < 0 due to less rotational freedom, so - TΔSsys > 0
ΔHsys < 0 as high energy pi bonds converted to more stable sigma bondΔG = ΔHsys - TΔSsys = (-) + (+)
The sign of ΔG (spontaneity) depends on temperature. Low temperature will favor product.

15. ΔG: Exergonic
Free energy change affects the equilibrium constant of reaction: ΔG = -R T lnK
If a process at a given temperature is calculated to have a negative ΔG, the process is exergonic
It will be spontaneous and favor the products (K > 1)

16. ΔG: Endergonic
If a process at a given temperature is calculated to have a (+) ΔG, the process is endergonic
It will be NONspontaneous and favors the reactants
Equilibrium constant K < 1

17. ΔG and Equilibrium
For an exergonic process with a (-) ΔG, reaction will eventually reach equilibrium
A spontaneous process will simply favor the products
The greater the magnitude of a (-) ΔG, the greater the equilibrium concentration of products

18. Equilibria Constant
An equilibrium constant (Keq) is used to show the degree to which a reaction is product or reactant favored
Keq, ΔG, ΔH, and ΔS are thermodynamic terms.

19. Dynamic Equilibrium In any reaction, collisions are necessary
As [A] and [B] decrease collisions between A and B will occur less often
As [C] and [D] increase, collisions between C and D will occur more often
The more often C and D collide, the more often collisions will occur with enough free energy for the reverse reaction to take place
Recall that equilibrium is dynamic and occurs when the forward and reverse reaction rates are equal

20. How fast reaction progress: Kinetics
The reaction rate (the number of collisions that will result in product production in a given period of time) is affected
The concentrations of the reactants
The Activation Energy
The Temperature
Geometry and Sterics
The presence of a catalyst

21. Rate Law Equations
To quantify how much the reactant concentration affects the rate of reaction, the Rate Law equation is used
The degree to which a change in [reactant] will affect the Rate is known as the order.
The order is represented by x and y in the Rate Law equation

22. Example of Rate Law. I
Consider a generic reaction that is known to be first order with respect to A and zero order with respect to B: A + B  C + D
Rate Law: rate = k [A]
Rate ______________ if [A] were doubled
Rate ______________ if [B] were doubled

23. Example of Rate Law. II
Consider a generic reaction that is known to be first order with respect to A and first order with respect to B: A + B  C + D
Rate Law: rate = k [A][B]
Rate ______________ if [A] were doubled
Rate ______________ if [B] were doubled

24. Activation Energy Affects Rates
Activation Energy Ea: the energy barrier for reactant to overcome to become product.
Arrhenius equation:
Rate constant
k = A exp(-Ea/RT)
Mainly the energy to break/weaken the bond(s) in reactant
Free
energy
(G)

25. Low activation energy increases rate
lower Ea allows more molecules to overcome barrier
Free
energy
(G)
Free
energy
(G)

26. High temperature increases rate
Temperature is a measure of a system’s average kinetic energy
Higher temperature renders more molecules having the energy higher than activation energy for reaction with lower Ea.

27. Geometry Affect Rates Example: hydroxide ion attack C-Br bond Free
energy
(G)

28. Catalyst reduces activation energy
Catalyst offers alternative reaction pathway to lower activation energy
Free
energy
(G)

29. Summary: Factors that Affect Rates
Higher temperature speeds up reactions. As temperature increases, equilibrium is sooner reached and the rxn that is more exergonic (G < 0) is more favored.
Reaction with lower activation energy Ea is typically faster. Catalyst speeds up reaction by lowering the activation energy
Steric effect: Generally speaking, larger/more atoms nearby rxn center slows down reaction rate.

30. Energy Diagrams Kinetics (Ea) vs. Thermodynamics (ΔG)
Rate = A exp(-Ea/RT) vs. Keq = exp(-ΔG/RT)
Free
energy
(G)
Free
energy
(G)

31. Kinetically Favored Pathway
Among competitive reaction pathways (A + B  C + D vs. A + B  E + F)
If one pathway has lower activation energy, it is kinetically favored.
At lower temperature where all reactions are slower, such pathway is more favored, thus the major products are E and F.
Free energy (G)

32. Thermodynamically favored Pathway
Among competitive reaction pathways,
If a pathway releases more free energy, it is thermodynamically favored.
At higher temperature where all reactions are reaching equilibrium, such pathway is more favored (products C and D are the major products)
Free energy (G)

33. Kinetics (Ea) vs Thermodynamics (G)
At low temperature, reaction with lower Ea proceeds faster
At high temperature, both forward and reverse reaction will speed up, readily reaching equilibrium.
Reaction A + B  C + D has both lower Ea and more negative G, thus is favored at both high and low temperatures (C and D is always favored at any temperature)
Free
energy
(G)

34. Transition States A transition state occurs at an energy maxima
Transition states exist for a fleeting moment; they cannot be isolated or directly observed
Ananlogy: A snapshot of a high-jumper over the bar.
Free
energy
(G)

35. Intermediates An intermediate occurs at an energy minima
Intermediates often exist long enough to be observed because bonds are NOT in the process of breaking or forming
Free
energy
(G)

36. Transition States vs Intermediates
Free
energy
(G)

37. The Hammond Postulate
Two points on an energy diagram that are closer in energy should be more similar in structure
Free
energy
(G)

38. Structure: Transition state
Structure of TS is close to PRODUCT vs. REACTANT
Free
energy
(G)
Free
energy
(G)

39. Practice: The Hammond Postulate
Draw a reaction coordinate diagram for the generic exergonic reaction sequence below. Label the axis, reactants, products, intermediates, and transition states A  B + C C + D  E Net reaction: A + D  B + E

40. Electrostatic Interaction in Reaction
Electrostatic interaction plays an important role in many organic reactions
Positive (+) charged (full or partial) positively charged atom/ion is attracted by negatively (-) charged (full or partial) charged atom/ion
Electronegativity effect: C+ in CH3Cl vs. C- in LiCH3

41. Nucleophiles
When an atom carries a formal or partial negative charge and an available pair of electrons, it is considered a nucleophile
It will love to attack a nucleus X+ .
Examples of common nucleophiles
Nucleophile is Lewis Base

42. Electrophiles
When an atom carries a formal or partial positive charge and can accept a pair of electrons, it is considered a electrophile
It will love available electrons (LP or Anion)
Examples: C+ -X (X = halide), carbocation C+
Electrophile is a Lewis Acid

43. Find Electrophilic vs. Nucleophilic sites
Label all of the nucleophilic and electrophilic sites on the following molecule
Lone pair of electrons on the δ- oxygen is slightly nucleophilic
δ+ charge on carbon is electrophilic as its pi electrons can shift to the oxygen if it is attacked by a nucleophile
Lone pair of electrons on the δ- nitrogen is slightly nucleophilic (slightly more than oxygen in general, because nitrogen can more effectively stabilize a
+ charge that forms when it attacks an electrophile

44. Arrow Pushing in Mechanisms
We use arrows to show how electrons move when bonds break and form
There are four main ways that electrons move in ionic reactions
Proton Transfers (Acid/Base): REVIEW
Nucleophilic Attack
Loss of a Leaving Group
Rearrangements

45. I. Proton (H+) Transfers
Protonation (Ch. Acid/Base): base binds H+ with lone pair electrons. Example:
Deprotonation: (“–H+” over the reaction arrow). or

46. Multiple arrows in Proton Transfers
Such electron flow can also be viewed as a proton transfer combined with resonance

47. II. Nucleophilic Attack
Arrow from Nucleophilic site (lone pair, -) toward Electrophilic site (+) , forming bond
The tail of the arrow starts on the electrons (- charge)
The head of the arrow ends on a nucleus (+ charge)
The electrons end up being shared (forming bond) rather than transferred

48. Multiple arrows in Nucleophilic Attack
Nucleophilic attack may occur in two arrows
Nucleophile: alcohol (lone pair and Oδ- )
Electrophile: Cδ+=O
The second arrow is needed to maintain octet, as if a resonance arrow.

49. III. Loss of a Leaving Group
Loss of a leaving group occurs when a bond breaks and one atom from the bond takes BOTH electrons
Tail of arrow on the bond to be broken
Head of arrow toward the group or atom (gaining the pair of electrons)
Similar to Deprotonation, but here leaving group TAKES both electrons.

50. Multiple arrows in Loss of Leaving Group
For the molecule below, draw the structure that will result after the leaving group is gone

51. Practice: Fill Arrow Pushing
Fill in necessary arrows: Watch the change first!

52. Carbocation stabilized by Hyperconjugation
Carbocations are common reaction intermediates
can be stabilized by neighboring groups through slight orbital overlapping (hyperconjugation)
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

53. More Alkyl Group more hyperconjugation
More alkyl groups (R) better stabilize carbocation
If a carbocation can INTRAmolecularly rearrange to become more stable, it will likely do so before reacting with a nucleophile.
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

54. Carbocation Rearrangements
Rearrangement involves bond breaking and bond forming
Two types of carbocation rearrangement are common
Hydride shift
Methyl shift
Shifts can only occur from an adjacent carbon.
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

55. Summary of Arrow Pushing Patterns: A. Proton Transfer; B
Summary of Arrow Pushing Patterns: A. Proton Transfer; B. Nucleophilic Attack; C. Loss of Leaving Group; D. Rearrangements
Fill the arrows and recognize the changes in the following mechanism

56. Combining Arrow Pushing Patterns
Commonly a single step in a mechanism may include more than one arrow pushing pattern
Draw the arrows in the following single step reaction and Identify the patterns (A. Proton Transfer; B. Nucleophilic Attack; C. Loss of Leaving Group; D. Rearrangements)

57. General Arrow Pushing Rules
Key rules for drawing reasonable mechanisms:
1. The arrow starts ON A PAIR OF ELECTRONS (a bonded pair or a lone pair). From Lewis base.
Don’t make the mistake of starting an arrow on a nucleus!
Incorrect arrows:

58. Arrow Pushing Rule 2
The arrow ends ON A NUCLEUS (electrons become a lone pair) or between two NUCLEI (electrons move into position to become a bond)

59. Arrow Pushing Rule 3
Avoid breaking the octet rule by double arrows (). NEVER give C, N, O, or F more than 8 valence electrons

60. The Four Ways Arrow Pushing:
Draw arrows that follow the 4 key patterns outlined earlier
The arrow below is unreasonable. WHY?

61. Practice Arrow Pushing
Fill in necessary arrows: Watch the change first! (You should use CURVED arrow)

62. More Arrow Pushing

63. Practice: Arrow Pushing
identify the unreasonable arrows and correct them:

64. Additional Practice Problems
Reactants A and B can react by two different pathways. Pathway 1 is thermodynamically favored, and pathway 2 is kinetically favored. Draw a reaction coordinate diagraph to illustrate the relative energies and predict which pathway will be favored at low temperatures versus higher temperatures.

65. Practice: Applying Arrow Movement
Write the structure of products:

66. Additional Practice Problems
Label all of the nucleophilic and electrophilic sites on the following molecules

67. Proton (H+) Transfers
Protonation (Ch. Acid/Base): base binds H+ with lone pair electrons. Example:
Deprotonation: (“–H+” over the reaction arrow). or

68. Proton Transfers
Multiple arrows may be necessary to show the complete electron flow when a proton is exchanged
Such electron flow can also be thought of as a proton transfer combined with resonance

69. Nucleophilic Attack
Nucleophilic attack may appear to occur in two steps
Here alcohol is the nucleophile. It attacks a carbon with a δ+ charge
The second arrow shows the flow of negative charge to maintain octet.
The second arrow could be thought of as a resonance arrow.

70. Loss of a Leaving Group
Loss of a leaving group occurs when a bond breaks and one atom from the bond takes BOTH electrons
For the molecule below, draw the structure that will result after the leaving group is gone

71. Carbocation Rearrangements
Two types of carbocation rearrangement are common
Hydride shift
Methyl shift
Shifts can only occur from an adjacent carbon.
Copyright © 2015 John Wiley & Sons, Inc. All rights reserved.
Klein, Organic Chemistry 2e

72. Summary of Arrow Pushing Patterns: Nucleophilic Attack/Loss of a Leaving Group/Proton Transfers/Rearrangements
What are the steps in the following mechanism?

73. Combining Arrow Pushing Patterns
Many times a single step in a mechanism will include more than one arrow pushing pattern
Identify the patterns below
There are hundreds of mechanisms that involve these key patterns

74. 6.10 Arrow Pushing Rules Key rules for drawing reasonable mechanisms:
The arrow starts ON A PAIR OF ELECTRONS (a bonded pair or a lone pair)
Don’t make the mistake of starting an arrow on a nucleus! Both arrows below are incorrect. WHY?

75. Arrow Pushing Rule 2 Starting from one lone pair electrons
The arrow ends ON A NUCLEUS (electrons become a lone pair) or between two NUCLEI (electrons move into position to become a bond)

76. Arrow Pushing Rule 3 A few key rules should be followed
Avoid breaking the octet rule by double arrows (). NEVER give C, N, O, or F more than 8 valence electrons

77. The Four Ways Arrow Pushing: A few key rules should be followed
Draw arrows that follow the 4 key patterns we outlined
The arrow below is unreasonable. WHY?

78. Answer: Arrow Pushing
Fill in necessary arrows: Watch the change first! (You should use CURVED arrow)

79. Answers
Label all of the nucleophilic and electrophilic sites on the following molecule 1 7 2 5 3 4 6
Lone pair of electrons on the δ- oxygen is slightly nucleophilic
δ+ charge on carbon is electrophilic as its pi electrons can shift to the oxygen if it is attacked by a nucleophile
Lone pair of electrons on the δ- nitrogen is slightly nucleophilic (slightly more than oxygen in general, because nitrogen can more effectively stabilize a
+ charge that forms when it attacks an electrophile

80. Answers
Label all of the nucleophilic and electrophilic sites on the following molecule 1 7 2 5 3 6 4
This is a very electrophilic site. The + charged oxygen is very strongly attracting pi electrons from the carbon giving it a very large δ+ charge.
In a minor but significant resonance contributor, this carbon carries a negative charge and a lone pair of electrons. Thus, it is a highly nucleophilic site.
Lone pair of electrons on the significantly δ- oxygen is nucleophilic