Transcript Ch 6 Lecture 2

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
HS
B.
-
H
H
Bu C Br
H3C
R
C
HS
S
Bu
CH3
Br-
+
How would we make the R thiol? (2-steps)
H
-
I
Bu C Br
H3C
R
H
C
I
S
Bu
CH3
+
-
Br
SH-
H
Bu C SH
H3C
R
C.
If multiple C* present, only the reacting center is affected
Me
II.
Me
H
Br
H
H
H
Cl
xs CN
-
Me
CN
H
H
H
CN
H
Me
Me
2S, 3R
Meso
Me
H
Br
Et
H
I
H
Et
H
I
Me
Me
2S,3R
2R,3R
Leaving Group Ability
A.
B.
LG Ability = how easy the LG can be replaced by a Nu
What makes a good leaving group?
1) Stabilize negative charge: I- > Br- > Cl- > F2) 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
O
O
CH3O
S
O-
O
Methyl sulfate
CH3
S
O
O-
O
mesylate
CF3
S
O
O-
CH3
S
O
triflate
O
tosylate
O-
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 Fb) 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- > CH3c) 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
O
CH3 DMF
Methanol
C N
Dimethylformamide
CH3OH
Polar
CH3
H
Polar
Protic
Aprotic
6)
D.
What kind of solvent is best to do SN2 reaction?
Role of Polarizability
1) Larger atoms are more polarizable and more nucleophilic = faster reaction
2) Larger orbitals allow better overlap with backside lobe
E.
F.
Role of Steric effects on the Nucleophile
1) Bulky nucleophiles react slower CH3O2) Smaller nucleophiles react faster
CH3
+
CH3
C O
+
CH3I
CH3OCH3
Mostly
CH3
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
O
b) Use right solvent
c) Use excess of Nu
+
NaI
Cl
d) Precipitate out the LG to remove it from the reaction
I
+
IV. Steric Effects of the Electrophile: Bulk near the electrophile slows reaction
A.
B.
C.
Branching at the electrophilic Carbon
Chain Length
Branching at other carbons
I
NaCl
A.
Branching at electrophilic Carbon
B.
Chain Length
C.
Branching at adjacent carbons