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

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

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

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

Bond Dissociation Energies High BDE for stronger bond

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

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

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

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)

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

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

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

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

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.

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)

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

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

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.

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

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

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

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

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

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)

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

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.

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

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

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.

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

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)

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)

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)

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)

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)

Transition States vs Intermediates Free energy (G)

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

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

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

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

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

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

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

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

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

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

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

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.

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.

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

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

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

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

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

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

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)

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:

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)

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

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

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

More Arrow Pushing

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

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.

Practice: Applying Arrow Movement Write the structure of products:

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

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

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

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.

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

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

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

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

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?

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)

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

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?

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

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

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