Ch 6 Lecture 2 More SN2

I. Synthesis using SN2 Reactions

A. R S conversions

1) We know SN2 interconverts stereochemistry

2) We can use this to produce the enantiomer we want in one step

B. How would we make the R thiol? (2-steps)

H

CBr

H3CBu

HS-H

CHS

CH3

Bu + Br-

R S

H

CBr

H3CBu

I-H

CI CH3

Bu + Br-

R S

SH- H

CSH

H3CBu

R

C. If multiple C* present, only the reacting center is affected

II. Leaving Group AbilityA. LG Ability = how easy the LG can be replaced by a Nu

B. What makes a good leaving group?

1) Stabilize negative charge: I- > Br- > Cl- > F-

2) Polarizability (size/charge) of I- allows it to readily handle (-)

3) F is a very poor leaving group: (high bond strength, low polarizability)

4) Other good leaving groups: Sulfates and Sulfonates

Me

ClH

HH

H Br

Me

Me

HCN

HH

CN H

Me

Me

HEt

BrH

Me

Me

HEt

HI

Me

xs CN-

2S, 3R Meso

I

2S,3R 2R,3R

S

O

O

CH3O O- S

O

O

CH3 O- S

O

O

CF3 O- S

O

O

O-CH3

Methyl sulfate mesylate triflate tosylate

C. Rules for predicting LG Ability

1) Weak bases are best (conj. bases of strong acids)

a) HI > HF, so I- is better LG, than F-

b) Sulfates and Sulfonates are conj. bases of very strong acids

2) How do we predict Acid Strength

a) Size of A- (Larger A- distributes charge more easily)

b) Electronegativity of A-: HF>H2O>NH3>CH4

F- > OH- > NH2- > CH3-

c) Resonance structures help distribute (-)

Draw Resonance Structures of Sulfate and sulfonate examples above

III. Nucleophilicity and SN2

A. Nucleophilicity = how much species needs (+)

1) Negatively charged species more reactive than neutral species: OH- > H2O

2) Nucleophilicity decreases from left to right on periodic table

a) Stronger bases are better nucleophiles

b) NH2- > OH- > NH3 > F- > H2O

B. Solvation effects on Nucleophilicity

1) F- > Cl- > Br- > I- as nucleophiles according to Basicity

2) Basicity works across a row, but not down a column. Why?

3) Smaller anions are better solvated

a) Increased charge/volume ratio

b) Decreases reactivity

4) Larger anions are less solvated

a) Low charge/volume ratio

b) Increased reactivity

C. Role of the Solvent in SN2

1) Protic vs Aprotic Solvents

a) Protic solvents have ionizable protons: CH3OH, H2O, NH3 (+H—Y-)

b) Aprotic solvents have no ionizable protons: CH3CN, EtOEt, Acetone

2) Polar vs. Nonpolar Solvents

a) Polar covalent bonds must lead to overall dipole = polar

Water, alcohols, acetonitrile, acetone

b) Nonpolar = small or no net dipole: alkanes, ethers

3) Protic solvents reduce the reactivity of Nucleophiles by interacting with the negatively charged Nu

4) Aprotic solvents can still dissolve Nucleophiles, but they don’t interact so strongly, leading to more reactivity

5) Cl- is 1,200,000 times more reactive (with MeI) in DMF than methanol

6) What kind of solvent is best to do SN2 reaction?

D. Role of Polarizability

1) Larger atoms are more polarizable and more nucleophilic = faster reaction

2) Larger orbitals allow better overlap with backside lobe

CH3OH NCH3

CH3

C

O

H

MethanolPolarProtic

DMFDimethylformamidePolarAprotic

E. Role of Steric effects on the Nucleophile

1) Bulky nucleophiles react slower

2) Smaller nucleophiles react faster

F. SN2 reactions are reversible

1) LG can also serve as Nucleophile to reverse reaction

2) How do you keep it going in one direction

a) Choose nucleophile that is much faster than LG

b) Use right solvent

c) Use excess of Nu

d) Precipitate out the LG to remove it from the reaction

IV. Steric Effects of the Electrophile: Bulk near the electrophile slows reactionA. Branching at the electrophilic Carbon

B. Chain Length

C. Branching at other carbons

C

CH3

CH3

CH3 O-+ CH3ICH3O-

+

MostlyCH3OCH3

Cl + NaI I + NaCl

O

I

A. Branching at electrophilic Carbon

B. Chain Length

C. Branching at adjacent carbons