5.9 Resolution of Enantiomers - a process of separating a racemate into pure enantiomers.

Crystallization

Chiral resolving agents. The enantiomers of the racemate must be temporarily converted into diastereomers.

H H (R)(R) + H NH H NH2 N H3O 2 H (R)(R) C • (S)(S) (S)(S) C H NH2 N H C CO H H3C (R)(R) CO2 N 3 2 C (S)(S) (S)(S) (R)(R) H (R)-(–) H3C (R)(R) CO2H N (R)(R) H + (-)-sparteine 2N HH H C H (R)(R) N HH N + 2 H3C (S)(S) CO2H 2N HH H3O (S)(S) (S)(S) C C • H C CO H N 3 2 H3C (S)(S) CO2 (R)(R) H (S)-(+)

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Chapter 6 Chemical Reactivity and Mechanisms 6.1 Enthalpy (ΔH) - the heat (energy) exchange between the reaction and its environment at constant pressure

Bond breaking processes require heat from the environment. Homolytic: symmetrical bond breaking process

Heterolytic: unsymmetrical bond breaking processes

Bond dissociation energy (ΔH°) – energy required for homolytic cleavage of a covalent bond. Table 6.1 (p. 238)

Heat of reaction (ΔH°) - total enthalpy change bond during a reaction. ΔH°products – ΔH°reactant = ΔH°reaction

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59 Some bond dissociation energy values from Table 6.1 (p. 238)

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H H H H Br CC + H Br CC H H H H H C=C 632 KJ/mol (σ + π bonds) C–C – 368 KJ/mol (σ bond) H–Br 368 KJ/mol C–H – 410 KJ/mol C-Br – 285 KJ/mol + 1000 KJ/mol –1063 KJ/mol – 63 KJ/mol

Exothermic = product are favored Endothermic = reactant are favored Heat is absorbed for the reaction to proceed Heat is released 120

60 Enthaphy (ΔH°): heat of reaction Change in total bond energies during a reaction

ΔH° < 0: bond energies of the products are stronger (more stable) than those of the reactants. The reaction is favored, heat is released, exothermic. ΔH° > 0: bond energies of the products are weaker (less stable) than those of the reactants. The reaction is disfavored, heat is absorbed, endothermic.

6.2 Entropy (ΔS°): Entropy change: measure of molecular disorder

ΔS° < 0: disorder is decreased (more order), disfavored ΔS° > 0: disorder is increased (less order), favored

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6.3 Gibbs Free Energy ΔG° = ΔH° - TΔS°

ΔG° < 0: free energy change for the reaction is favorable - spontaneous – exergonic ΔG° > 0: free energy change for the reaction is unfavorable. - not spontaneous – endergonic

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61 6.4 Equilibria H H H H Br CC + H Br CC H H H H H

[CH3CH2Br] Keq = [H2C=CH2] [HBr]

Keq tells us which side of the equilibrium arrows is energetically more favorable. if: Keq > 1, then [products] is greater than [reactants] and products are favored

Keq < 1, then [reactants] is greater than [products] and reactants are favored

ΔG° = ΔH° - TΔS° -3 -1 -1 ΔG° = -RT ln Keq R= 8.314 x 10 KJ • mol • °K

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H Cl ΔG° = -2.0 KJ/mol Cl H

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62 6.5 Kinetics Thermodynamics (equilibria, Gibbs Free Energy) can only tell us the position of an equilibrium (Keq) or if a reaction is theoretically possible. It does not tell us how fast a reaction occur.

Rate = how fast (or slow) a reaction will occur

Rate Equations – the rate of a reaction can be expressed as the time-dependent disappearance of reactants or appearance of products.

Reactions require molecular collisions of sufficient energy (Ea) and the proper orientation.

‡ Activation Energy (Ea, ΔG ): Energy difference between reactants and the transition state. The rate of a reaction depends on the activation energy (Ea)

Small Ea - fast reaction rate Large Ea- slow reaction rate

ΔG° ΔG°

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63 Temperature – Reaction rates increase as temperature increases. • increasing the temperature increases the kinetic energy of the reactants • increasing the temperature increases the frequency of molecular collisions

Sterics – effects of bulk. Steric congestion slows reactions.

Catalysts – substance that increases the reaction rate but is not consumed in the overall reaction. Catalysts increase rates by lowering the Ea. Catalysts do not affect the free energy change of the reaction (ΔG°).

ΔG°

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6.6 Reading Energy Diagrams Kinetics vs Thermodynamic

Transition States vs Intermediates Transition state – structure corresponding to maxima on the reaction coordinate. Intermediate – structure corresponding to a minima on the reaction coordinate, between the reactants and products

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64 Ea2

Ea1 Ea3 ΔG°2 ΔG°1

reactants ΔG°3

ΔG°

products

Transition states can not be isolated or “trapped.” Intermediates in principle, can be isolated or “trapped.”

What is the structure of a transition state?

How do the structures of the reactants and products affect Ea?129

The Hammond Postulate – an intuitive relationship between rate

(Ea) and product stability (ΔG°). The structure of the transition state more closely resembles the nearest stable species (i.e., the reactant, intermediate, or product).

For an endothermic reaction (ΔG° > 0), the TS is nearer to the product. The structure of the TS more closely resembles that of the product. Therefore, factors that stabilize the product will also stabilize the TS leading to that product.

For an exothermic reaction (ΔG° < 0), the TS is nearer to the reactant. The structure of the TS more closely resembles that of the reactants.

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65 6.7 Nucleophiles and Electrophiles Reactive species for polar (ionic) reactions

Electron rich (δ–) sites in a functional group of one molecule react with an electron-poor (δ+) sites of another functional group

Electrophile: electron poor (lover of electrons) Nucleophile: electron rich (lover of nuclei)

Note the similarity to Lewis acid-base definition Lewis acid: electron pair acceptor (electrophile) Lewis base: electron pair donor (nucleophile) + (δ+) - (δ -) A + B A-B electrophile nucleophile – – CC Some nucleophiles H3N H2O HO X

δ+ O δ– + + Some electrophiles H H3C–X C C δ+ 131

6.8 Mechanisms and Arrow Pushing Nucleophilic Attack – nucleophilic center adding to (attacking) an electrophilic center.

Loss of a Leaving Group – Nucleophilic addition often results in the loss of an atom or group (the leaving group) from the electrophile. The leaving group departs with an electron pair.

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66 Proton Transfer – it is common for protons to be shuffled (transferred) between atoms during reactions. This is often a crucial part of the reaction mechanism.

Rearrangements – a single reactant undergoes bond reorganization to give a product that is an isomer of the reactant

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6.9 Combining the Patterns of Arrow Pushing

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67 6.10 Drawing Curved Arrows (adapted from slide 39, Chap. 2)

1. Curved arrows show the movement (flow) of electrons during bond breaking and/or bond making processes (mechanism). The movement of an electron pair is denoted by a curved double headed arrow for polar reactions. The foot of the arrow indicates where the electron pair originates (nucleophile for polar mechanisms), the head of the arrow shows where the electron pair ends up (electrophile for polar mechanisms).

double-headed arrow (electron pair) 2. If an electron pair from a nucleophile moves in on (attacks) an electrophilic atom, another electron pair must leave so that the electrophilic atom does not exceed a full valance of eight electrons. A common exceptions is when

the electrophilic atom has an incomplete valance (R3C+).

3. The arrows completely dictate the Lewis structure of the product.

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6.11 Carbocation Rearrangements – a –H (hydride) or –CH3 (methyl) from a carbon adjacent to a carbocation may migrate with its electron pair to the cationic carbon to generate an isomeric carbocation. The rearrangement will occur if the new carbocation is more stable than the original.

Carbocation stability: Increased substitution stabilizes carbocations through:

Inductive Effects: shifting of electrons in a σ-bond in response to the electronegativity of a nearby atom (or group). Carbon is a good electron donor. Substitution can stabilize carbocations by donating electron density through the σ -bond. R R R H + + + C + C C C R R R H H H H H 3°: three alkyl groups 2°: two alkyl groups 1°: one alkyl group methyl: no alkyl groups donating electrons donating electrons donating electrons donating electrons

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68 Hyperconjugation: The C-H σ -bond on the neighboring carbon lines up with the vacant p-orbital and can donate electron density to the carbon cation. This is a “bonding” interaction and is stabilizing. More substituted carbocations have more possible hyperconjugation interactions.

H

C C

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6.12 Reversible and Irreversible Reaction Arrows All reactions are in principle reversible. The mechanism of the reverse reaction is identical to that of the forward reaction, only in reverse (Principle of Microscopic Reversibility).

Nucleophilic attack – is potentially reversible if the nucleophilic group is also capable of acting as a leaving group

Leaving groups – many of the properties of a good leaving group also makes them good nucleophiles.

Proton transfer – differences in pKa between the proton donor and acceptor gives an indication of reversibility; however, low concentrations of a protonate species (unfavorable equlibrium) can still be useful.

Carbocation rearrangements – the equilibrium between a carbocation and its rearrangement product is reflective of their relative stability.

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