SN2 Reaction: Effect of Steric Hindrance
SN2 Reaction: Effect of Steric Hindrance Color pictures: web.chem.ucla.edu/~harding/SN2sterics.html In an SN2 reaction, the nucleophile must approach the carbon-leaving group bond from the backside. What is the effect on the SN2 reaction rate when the crowding increases at this carbon? Models are useful when considering this idea. The space filling models shown below represent the van der Waals radii of the atoms within the molecules. These models provide a reasonable representation of the true spatial appearance of molecules. The ball and spoke models are also shown to give an alternate view of the same molecule. The molecules are viewed along the C-I bond, with the iodine pointing away. This is the same view as the nucleophile has as it approaches along the backside of the C-I bond. Note that the carbon bearing the iodide becomes less visible as hydrogens are replaced by methyls. Electrophile
Ball and Stick Model
Space Filling Model
Methyl iodide CH3I methyl
Ethyl iodide CH3CH2I primary (1o)
2-Iodopropane (isopropyl iodide) (CH3)2CHI secondary (2o)
2-iodo-2-methylpropane (tert-butyl iodide) (CH3)3CI tertiary (3o)
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Lecture Supplement: Ionic Substitution – SN2
Solvents Solvent: A substance in which other substances are dissolved. Role of Solvent in Organic Reactions Dissolve reactants so they can mingle and achieve transition state orientation Disperse heat Precipitate a product, driving equilibrium to the right Other laboratory considerations
• • • •
Demonstration: mix dry
Alka-seltzer tablets O
HO
CO2H O + NaHCO3
HO
OH Citric acid (a solid)
Sodium bicarbonate (a solid) mix aqueous
Solvent Effects on SN2 Reaction Rate Reaction rate α Ea = energy difference between reactants and transition state
Ea (A)
Ea (A) Ea (B) Energy
Energy
solvent A
solvent B
Reaction coordinate
Solvent B provides good stabilization of reactants but little for transition state
Ea (C)
solvent A solvent C
Reaction coordinate
Solvent C provides little stabilization of reactants but lots for transition state
Ea (B)
Ea (A)
Ea (C)
Ea (A)
rate B
rate A
rate C
rate A
Lecture Supplement: Ionic Substitution – SN2
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How Does Solvent Stabilize (Interact with) Reactants and Transition State? → Noncovalent forces (electrostatic effects)
Review Chem 14C
→ Stronger interaction (larger charges) = more stabilization • Dipole-dipole • Ion-dipole • Hydrogen bonding • Van der Waals (weak; insignificant stabilization; ignored for simplicity)
Cl surrounded by CH3OH: solvent shell provides solvation for Cl . Important Solvent Properties Dielectric constant (ε): Ability to insulate unlike charges from each other •
Higher ε = greater number and magnitude of δ+/δ- on solvent = stronger attraction to solute molecules
•
Strength of interactions (stabilization): +/- > δ+/δ- > neutral
•
Greater number and/or magnitude of polar bonds = higher ε Example: CH3OH (ε = 33) versus CH3CH2OH (ε = 25)
•
ε > 20 = polar solvent; ε < 20 = nonpolar solvent
Proticity: Ability to donate hydrogen atom for hydrogen bond
6
Review Chem 14C
•
Protic solvent: can donate hydrogen atom (O-H in common solvents)
•
Aprotic solvent: not protic
•
Example: CH3OH (protic) versus CH2Cl2 (aprotic)
Lecture Supplement: Ionic Substitution – SN2
Structures and Properties of Common Organic Solvents Polar solvents (ε > 20) Name
Structure
Proticity
Dielectric constant
O
protic
80
aprotic
49
aprotic
37
protic
33
protic
25
aprotic
21
aprotic
9.1
aprotic
7.6
protic
6.2
Water H
Dimethylsulfoxide (DMSO) N,N-Dimethylformamide (DMF)
H
O S CH3
CH3
O
H
N(CH3)2
Methanol (MeOH)
CH3
Ethanol (EtOH)
CH3CH2
OH
OH
O
Acetone (2-propanone) CH3
CH3
Nonpolar solvents (ε < 20) Dichloromethane (methylene chloride)
ClCH2Cl
Tetrahydrofuran (THF) O
O
Acetic acid (HOAc) CH3
OH
Ethyl ether
CH3CH2OCH2CH3
aprotic
4.3
Hexane
CH3(CH2)4CH3
aprotic
1.9
What Facts Must I Know About Solvents? •
Know structures, but no need to memorize.
•
Know relationship between structure and polarity.
•
Know if a given solvent is protic or aprotic.
•
Learn all this by doing lots of problems, with reference to this table when needed.
Lecture Supplement: Ionic Substitution – SN2
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Which Solvent is Best For SN2? Most common SN2 reaction involves charged ncuelophile, neutral electrophile, transition state with partial charges: R Nuc
+
R3C-LG
δ- Nuc
LG δ-
C R
Nuc
CR3 + LG
R
Fastest SN2 (lowest Ea): need solvent that stabilizes transition state (dispersed charges) more than reactants (Nuc), so nonpolar solvent is best. Problem: Nuc (usually ionic, such as NaCl) usually not very soluble in nonpolar solvents (such as hexane). Therefore need polar solvent (such as CH3OH or DMF) to dissolve Nuc. Hydrogen bonding stabilization must be sacrified to achieve transition state (costs energy) so use aprotic solvent. (SN2 slower, but usually not stopped in polar protic solvent such as CH3OH.)
= CH3OH = F hidden by CH3OH = CH3I In order for F and CH3I to reach the SN2 transition state, some CH3OH molecules (arrows) of the F solvent shell must move out of the way. This desolvation reduces the stability of F , raises Ea and slows the reaction.
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Lecture Supplement: Ionic Substitution – SN2
Is Hydrogen Bonding Equal for All Solvents and Nucleophiles? Effect of solvent (DMF versus CH3OH) on the SN2 reaction rate (k) of halide ion nucleophiles: 1
DMF (aprotic)
F
CH3OH (protic)
Cl 0
Br I
-1
-2 log k
I -3
-4
Br
-5 Cl -6
-7 F
Atomic radius conclusion:
Best SN2 solvent is....
Lecture Supplement: Ionic Substitution – SN2
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SN2 Examples Example #1: S-Adenosylmethionine (SAM): biological methylator
NH2 N O O
O
P
O
O
P O
NH2 N
N
O
O O
P
N
O
S
N
OH
Adenosyl triphosphate (ATP)
N
O
SN 2
O
N
O
O
N
CH3
NH3 HO
OH
OH
+ SAM
CH3
O
S
Methionine
O NH3
•
SAM involved in wide range of biological methylations.
•
Example: during the stress response, norepinephrine is converted into epinephrine (adrenaline):
N O
S
N
N
CH3 N
N
O
O
N
O NH3
NH3 HO
HO
OH
SN2
+
NH2
OH
+
Amine more nucleophilic than alcohol or phenol
OH HO
N
O S
N
O
NH2
NH2
This methyl transferred
OH HO
H N
CH3 norepinephrine HO
10
HO
epinephrine (adrenaline)
Lecture Supplement: Ionic Substitution – SN2
Example #2: Synthesis of zidovudine (AZT), an inhibitor of reverse transcriptase and anti-HIV drug.
3' oxygen must become N3 Stereochemistry must be changed But HO not a leaving group
O
5' oxygen must remain Ph3CO not a leaving group Ph3CO
O
AZT NH
OH
N
NH HO
O
N
O
O
O
N3 CH3SO2Cl HCl
O
H3C S Ph3CO
O
O
sulfonate = good leaving group
O
NH
N
NH
LiN3, DMF
O O
SN2 reaction
Ph3CO
N
O
O
O
N3
Lecture Supplement: Ionic Substitution – SN2
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Ball and Stick Model
Space Filling Model
Methyl iodide CH3I methyl
Ethyl iodide CH3CH2I primary (1o)
2-Iodopropane (isopropyl iodide) (CH3)2CHI secondary (2o)
2-iodo-2-methylpropane (tert-butyl iodide) (CH3)3CI tertiary (3o)
4
Lecture Supplement: Ionic Substitution – SN2
Solvents Solvent: A substance in which other substances are dissolved. Role of Solvent in Organic Reactions Dissolve reactants so they can mingle and achieve transition state orientation Disperse heat Precipitate a product, driving equilibrium to the right Other laboratory considerations
• • • •
Demonstration: mix dry
Alka-seltzer tablets O
HO
CO2H O + NaHCO3
HO
OH Citric acid (a solid)
Sodium bicarbonate (a solid) mix aqueous
Solvent Effects on SN2 Reaction Rate Reaction rate α Ea = energy difference between reactants and transition state
Ea (A)
Ea (A) Ea (B) Energy
Energy
solvent A
solvent B
Reaction coordinate
Solvent B provides good stabilization of reactants but little for transition state
Ea (C)
solvent A solvent C
Reaction coordinate
Solvent C provides little stabilization of reactants but lots for transition state
Ea (B)
Ea (A)
Ea (C)
Ea (A)
rate B
rate A
rate C
rate A
Lecture Supplement: Ionic Substitution – SN2
5
How Does Solvent Stabilize (Interact with) Reactants and Transition State? → Noncovalent forces (electrostatic effects)
Review Chem 14C
→ Stronger interaction (larger charges) = more stabilization • Dipole-dipole • Ion-dipole • Hydrogen bonding • Van der Waals (weak; insignificant stabilization; ignored for simplicity)
Cl surrounded by CH3OH: solvent shell provides solvation for Cl . Important Solvent Properties Dielectric constant (ε): Ability to insulate unlike charges from each other •
Higher ε = greater number and magnitude of δ+/δ- on solvent = stronger attraction to solute molecules
•
Strength of interactions (stabilization): +/- > δ+/δ- > neutral
•
Greater number and/or magnitude of polar bonds = higher ε Example: CH3OH (ε = 33) versus CH3CH2OH (ε = 25)
•
ε > 20 = polar solvent; ε < 20 = nonpolar solvent
Proticity: Ability to donate hydrogen atom for hydrogen bond
6
Review Chem 14C
•
Protic solvent: can donate hydrogen atom (O-H in common solvents)
•
Aprotic solvent: not protic
•
Example: CH3OH (protic) versus CH2Cl2 (aprotic)
Lecture Supplement: Ionic Substitution – SN2
Structures and Properties of Common Organic Solvents Polar solvents (ε > 20) Name
Structure
Proticity
Dielectric constant
O
protic
80
aprotic
49
aprotic
37
protic
33
protic
25
aprotic
21
aprotic
9.1
aprotic
7.6
protic
6.2
Water H
Dimethylsulfoxide (DMSO) N,N-Dimethylformamide (DMF)
H
O S CH3
CH3
O
H
N(CH3)2
Methanol (MeOH)
CH3
Ethanol (EtOH)
CH3CH2
OH
OH
O
Acetone (2-propanone) CH3
CH3
Nonpolar solvents (ε < 20) Dichloromethane (methylene chloride)
ClCH2Cl
Tetrahydrofuran (THF) O
O
Acetic acid (HOAc) CH3
OH
Ethyl ether
CH3CH2OCH2CH3
aprotic
4.3
Hexane
CH3(CH2)4CH3
aprotic
1.9
What Facts Must I Know About Solvents? •
Know structures, but no need to memorize.
•
Know relationship between structure and polarity.
•
Know if a given solvent is protic or aprotic.
•
Learn all this by doing lots of problems, with reference to this table when needed.
Lecture Supplement: Ionic Substitution – SN2
7
Which Solvent is Best For SN2? Most common SN2 reaction involves charged ncuelophile, neutral electrophile, transition state with partial charges: R Nuc
+
R3C-LG
δ- Nuc
LG δ-
C R
Nuc
CR3 + LG
R
Fastest SN2 (lowest Ea): need solvent that stabilizes transition state (dispersed charges) more than reactants (Nuc), so nonpolar solvent is best. Problem: Nuc (usually ionic, such as NaCl) usually not very soluble in nonpolar solvents (such as hexane). Therefore need polar solvent (such as CH3OH or DMF) to dissolve Nuc. Hydrogen bonding stabilization must be sacrified to achieve transition state (costs energy) so use aprotic solvent. (SN2 slower, but usually not stopped in polar protic solvent such as CH3OH.)
= CH3OH = F hidden by CH3OH = CH3I In order for F and CH3I to reach the SN2 transition state, some CH3OH molecules (arrows) of the F solvent shell must move out of the way. This desolvation reduces the stability of F , raises Ea and slows the reaction.
8
Lecture Supplement: Ionic Substitution – SN2
Is Hydrogen Bonding Equal for All Solvents and Nucleophiles? Effect of solvent (DMF versus CH3OH) on the SN2 reaction rate (k) of halide ion nucleophiles: 1
DMF (aprotic)
F
CH3OH (protic)
Cl 0
Br I
-1
-2 log k
I -3
-4
Br
-5 Cl -6
-7 F
Atomic radius conclusion:
Best SN2 solvent is....
Lecture Supplement: Ionic Substitution – SN2
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SN2 Examples Example #1: S-Adenosylmethionine (SAM): biological methylator
NH2 N O O
O
P
O
O
P O
NH2 N
N
O
O O
P
N
O
S
N
OH
Adenosyl triphosphate (ATP)
N
O
SN 2
O
N
O
O
N
CH3
NH3 HO
OH
OH
+ SAM
CH3
O
S
Methionine
O NH3
•
SAM involved in wide range of biological methylations.
•
Example: during the stress response, norepinephrine is converted into epinephrine (adrenaline):
N O
S
N
N
CH3 N
N
O
O
N
O NH3
NH3 HO
HO
OH
SN2
+
NH2
OH
+
Amine more nucleophilic than alcohol or phenol
OH HO
N
O S
N
O
NH2
NH2
This methyl transferred
OH HO
H N
CH3 norepinephrine HO
10
HO
epinephrine (adrenaline)
Lecture Supplement: Ionic Substitution – SN2
Example #2: Synthesis of zidovudine (AZT), an inhibitor of reverse transcriptase and anti-HIV drug.
3' oxygen must become N3 Stereochemistry must be changed But HO not a leaving group
O
5' oxygen must remain Ph3CO not a leaving group Ph3CO
O
AZT NH
OH
N
NH HO
O
N
O
O
O
N3 CH3SO2Cl HCl
O
H3C S Ph3CO
O
O
sulfonate = good leaving group
O
NH
N
NH
LiN3, DMF
O O
SN2 reaction
Ph3CO
N
O
O
O
N3
Lecture Supplement: Ionic Substitution – SN2
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