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WWU -- Chemistry
WWU -- Chemistry
WWU -- Chemistry
WWU -- Chemistry
R-CH 2-X
substrate
+ _
Nu
R-CH2-Nu
product
nucleophile
leaving group
R-CH 2-X +
O carboxylate
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R-CH 2-X
substrate
Nu
R-CH2-Nu
product
+
nucleophile
leaving group
_
R-CH 2-X +
NH 3 ammonia
_
R-CH2-NH3
R-CH 2-NH3 X
H-X
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R-CH 2-X
substrate
Nu
R-CH2-Nu
product
nucleophile
leaving group
X
_
H
R
d-
O
H H
C Br
d-
energy
.. __ O: .. R
C Br
OH R C H H Br
Reaction coordinate
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carbocation
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R C R
d+ R
d+
R
d-
Br
d+R
C R R Nu
energy
R C R
intermediate
R C R Nu
R
R R C R Br
Reaction coordinate
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WWU -- Chemistry
WWU -- Chemistry
H
R
d-
O
H H
C Br
d-
energy
.. __ O: .. R
C Br
OH R C H H Br
Reaction coordinate
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(R)- enantiomer
Inversion of configuration
.. O ..
CH3 C
+
Br
H Et
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(S) enantiomer
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0.008
unreactive! KI in Acetone at 25
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Fast
I-
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Relative Nucleophilicity
O CH3 C _ O _ O _ OH _ OCH3 _ I _ SH _ N C
CH3OH H2O
Increasing Nucleophilicty
1) In general, stronger bases are better nucleophiles 2) However, iodide doesnt fit that pattern (weak base, but great nucleophile!) 3) Cyanide is an excellent nucleophile because of its linear structure 4) Sulfur is better than oxygen as a nucleophile
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WWU -- Chemistry
CH3
OTs
Tosylate
Br
OBs
Retention of configuration
(S)-(+)-1-Phenyl-2-propanol
(S)-(+)-1-Methyl-2-phenylethyl tosylate
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Inversion of Configuration
CH3 CH2 O_ H CH3 C CH2 O O S O CH3
(S)
CH3 CH2 O
O S O O
_
(R)
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Aprotic solvents
These solvents do not have OH bonds in them. They complex the cation through the lone pairs on oxygen or nitrogen:
O Acetone H3 C CH3 O S O Dimethylf ormamide (DMF) H N CH 3 CH 3
H3 C
CH3
Acetonitrile
H3 C C N
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H3C
CH3
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Now that the Na+ is complexed, the OEt can react more easily
Et O
H3C Br
Et O CH3
Br
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Protic solvents
Typical protic solvents:
Water H O H O CH3 HOMe
abbreviations
Methanol
Ethanol
CH2 CH3
HOEt
Acetic acid
C CH3 O
HOAc
Formic acid
C H O
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WWU -- Chemistry
.. _ : Br : ..
carbocation
CH3 + H
R C R
d+ R
dR R C R O H intermediate H
Br
energy
R C R
+ R
intermediate
R
R R C R Br
R C R OH
Reaction coordinate
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WWU -- Chemistry
WWU -- Chemistry
H fast
H3C H
Pr O CH3 Et H fast
H3C
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R C R
d+ R
dR R C R O H intermediate H3C
Br
energy
R C R
+ R
intermediate
R
R R C R Br
R C R O-CH3
Reaction coordinate
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no reaction
1.00
11.6
Br
6 1.2 x 10
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CH3 CH3 C CH3 tertiary Br > CH3 CH CH3 secondary primary Br > CH3-CH2-Br > CH3-Br
CH3 CH3 C+ CH3 tertiary carbocation (very stable) three methyl groups CH3
+
CH CH3 CH3
+
CH 2
+
CH3
secondary carbocation
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Nucleophiles
Usually SN1 reactions are run in polar protic solvents; compounds with O-H groups. The polar protic solvent acts as BOTH nucleophile as well as the solvent. Common solvent/nucleophiles include: water, ethanol, methanol, acetic acid, and formic acid.
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A protic solvent acts as both a solvent and nucleophile in SN1 reactions solvolysis:
Water H O H O CH3 HOMe
abbreviations
Methanol
Ethanol
CH2 CH3
HOEt
Acetic acid
C CH3 O
HOAc
Formic acid
C H O
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H fast
Pr C H3C Et
CH3-O-H Fast
H3C H
Pr O CH3 Et H fast
H3C
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Leaving groups
Leaving groups are the same as in SN2 reactions:
Cl, Br, I, OTs are the usual ones.
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WWU -- Chemistry
If the reaction medium is KI or NaI in acetone, this demands an SN2 mechanism. If the reaction medium is AgNO3 in ethanol, this demands an SN1 mechanism. If the medium is basic, look for SN2.
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Effect of b-substitution
on SN2 reactivity
krel
1.0
0.65
0.15
b CH3
CH2 Br
Neopentyl bromide
0.000026
C
R2 R3
Nu Nu
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CH2-Br
benzyl bromide
80% Ethanol-water at 50
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CH2-Br
benzyl bromide
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60 C
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Cl
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>
H H C C CH2 Br H
>
>>
R CH2
Br
Br H C Br
3o
Benzyl Allyl
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>
>
R
CH Br
>>>
>> >
R R phenyl vinyl
Br H C Br
H H C C CH2 Br H
methyl
2o
3o
Can not undergo SN2
Benzyl Allyl
Inert!! No reaction!!
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a carbocation
2) CH3 CH3 C CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3
3)
OR CH3
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A Closer Look...
CH3 CH3 C CH3 CH3 CH3 C + CH CH3 CH CH3 + CH3 CH3 C + CH CH3 CH3
CH3
transition state
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Carbocation Rearrangement
CH
CH3
Carbocation Rearrangement
CH
CH3
Carbocation Rearrangement
CH
CH3
Carbocation Rearrangement
CH3
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Carbocation Rearrangement
CH3
Carbocation Rearrangement
CH3
Carbocation Rearrangement
CH3
Carbocation Rearrangement
CH3
_ O
_ + Br
_ Br
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..
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2) C
G C fast
G: C C Nu
G:
Nu :
X
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WWU -- Chemistry
Mustard gas
Mustard gas is a substance that causes tissue blistering (a vesicant). It is highly reactive compound that combines with proteins and DNA and results in cellular changes immediately after exposure. Mustard gas was used as a chemical warfare agent in World War I by both sides.
Cl S Cl S
Cl
Cl
Mustard gas
Cl Cl S
Cl S
O-Enzyme
Cl
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In-Class Problem
For the following reaction,
A) B)
Identify the mechanism of this reaction. Predict the product(s) of this reaction, and identify them as major or minor, if appropriate.
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SN2
Strong effect; reaction favored by methyl or primary halide Highly favored Does not occur
E1
Strong effect; reaction favored by tertiary halide Does not occur Occurs under solvolysis conditions or with strong acids Can occur in polar, protic solvents Very strong effect; reaction favored by polar, protic solvents Weak effect; reaction favored by weak base
E2
Strong effect; reaction favored by tertiary halide Occurs with strong base! Highly favored when strong bases (OH-, OR-) are used Favored when strong bases are used Strong effect; reaction favored by polar, aprotic solvent Strong effect; reaction favored by strong base Strong effect; reaction favored by good leaving group
Favored by good nucleophile in polar, aprotic solvents Strong effect; reaction favored by polar, aprotic solvents Strong effect; reaction favored by good nucleophile/weak base Strong effect; reaction favored by good leaving group
Nucleophile/Base
Leaving Group
WWU -- Chemistry