Ch 6 Lecture 2 More S N 2

1. Ch 6 Lecture 2 More SN2 • Synthesis using SN2 Reactions • R S conversions • We know SN2 interconverts stereochemistry • We can use this to produce the enantiomer we want in one step • How would we make the R thiol? (2-steps)

2. If multiple C* present, only the reacting center is affected • Leaving Group Ability • LG Ability = how easy the LG can be replaced by a Nu • What makes a good leaving group? • Stabilize negative charge: I- > Br- > Cl- > F- • Polarizability (size/charge) of I- allows it to readily handle (-) • F is a very poor leaving group: (high bond strength, low polarizability) • Other good leaving groups: Sulfates and Sulfonates tosylate mesylate triflate Methyl sulfate

3. Rules for predicting LG Ability • Weak bases are best (conj. bases of strong acids) • HI > HF, so I- is better LG, than F- • Sulfates and Sulfonates are conj. bases of very strong acids • How do we predict Acid Strength • Size of A- (Larger A- distributes charge more easily) • Electronegativity of A-: HF>H2O>NH3>CH4 F- > OH- > NH2- > CH3- • Resonance structures help distribute (-) Draw Resonance Structures of Sulfate and sulfonate examples above • Nucleophilicity and SN2 • Nucleophilicity = how much species needs (+) • Negatively charged species more reactive than neutral species: OH- > H2O • Nucleophilicity decreases from left to right on periodic table • Stronger bases are better nucleophiles • NH2- > OH- > NH3 > F- > H2O

4. B. Solvation effects on Nucleophilicity • F- > Cl- > Br- > I- as nucleophiles according to Basicity • Basicity works across a row, but not down a column. Why? • Smaller anions are better solvated • Increased charge/volume ratio • Decreases reactivity • Larger anions are less solvated • Low charge/volume ratio • Increased reactivity • Role of the Solvent in SN2 • Protic vs Aprotic Solvents • Protic solvents have ionizable protons: CH3OH, H2O, NH3 (+H—Y-) • Aprotic solvents have no ionizable protons: CH3CN, EtOEt, Acetone • Polar vs. Nonpolar Solvents • Polar covalent bonds must lead to overall dipole = polar Water, alcohols, acetonitrile, acetone b) Nonpolar = small or no net dipole: alkanes, ethers

5. Protic solvents reduce the reactivity of Nucleophiles by interacting with the negatively charged Nu • Aprotic solvents can still dissolve Nucleophiles, but they don’t interact so strongly, leading to more reactivity • Cl- is 1,200,000 times more reactive (with MeI) in DMF than methanol • What kind of solvent is best to do SN2 reaction? • Role of Polarizability • Larger atoms are more polarizable and more nucleophilic = faster reaction • Larger orbitals allow better overlap with backside lobe DMF Dimethylformamide Polar Aprotic Methanol Polar Protic

6. Role of Steric effects on the Nucleophile • Bulky nucleophiles react slower • Smaller nucleophiles react faster • SN2 reactions are reversible • LG can also serve as Nucleophile to reverse reaction • How do you keep it going in one direction • Choose nucleophile that is much faster than LG • Use right solvent • Use excess of Nu • Precipitate out the LG to remove it from the reaction IV. Steric Effects of the Electrophile: Bulk near the electrophile slows reaction • Branching at the electrophilic Carbon • Chain Length • Branching at other carbons

7. Branching at electrophilic Carbon

8. B. Chain Length

9. C. Branching at adjacent carbons