Download Effect of nucleophile on reaction

1
Effect of nucleophile on reaction
H
H
R
H
X
RDS
Nuc
R
H
H
H
R
Nuc
Nuc
H
H
R
X
RDS
H
H
Nuc
R
+ X
X
• Nucleophile not involved in RDS of SN1 so does not effect the reaction
•
•
(well obviously it controls the formula of the product!)
Nucleophile has a big effect on SN2
Large nucleophiles are poor in SN2 reactions due to steric hindrance
Large nucleophile (t-BuOH)
suffers steric interactions
Small nucleophile
(MeOH) can easily
approach
2
Nucleophile strength
• The stronger the nucleophile the faster / more efficient the SN2 reaction
• Nucleophilic strength (nucleophilicity) relates to how easily a compound can
donate an electron pair
• The more electronegative an atom the less nucleophilic as the electrons
are held closer
Anion more nucleophilic
than its neutral analogue
nucleophilic strength
R3C
(basicity)
C
electronegativity
nucleophilic strength
(basicity)
>
<
As we go down a group
both anions and neutral
atoms get more
nucleophilic - electrons
not held as tightly as size
increases
nucleophilic strength
HO
(basicity)
R2N
N
R NH2
> RO > F
< O < F
> R OH > R F
nucleophilic strength
(basicity)
H2O
As we move along a row
the electronegativity
increases and
nucleophilicity decreases
H2S
I
>
>
Br
>
>
H2O
Cl
>
F
3
Solvent effects
•
•
•
SN1
Intermediate - the carbocation - is stabilised by polar solvents
Leaving group stabilised by protic solvents (encourages dissociation)
Water, alcohols & carboxylic acids good solvents for SN1
Br
H
Br
H
O
O
H O
O
H
H
cation
stabilised
H
O
O
hydrogen
bonds
SN2
• Prefer less polar, aprotic solvents
• Less charge separation in TS‡ so less need for polar solvent
• Need aprotic solvent so that nucleophile is not solvated
H
H
O
O
H
H
I
H
H
O
H
O
H
CH3Br
H
H
O
O
H
H
I
δ–
needs H
H H
loss of
O
one H2O
H
δ–
Br
H
4
Leaving group
X
SN1
Nu
Nu or Nu
X
SN2
Nu
• Leaving group (X) is involved in RDS of both reactions - very
•
•
•
important
Better leaving group - faster both reactions are
Bond strength - stronger the bond worse the leaving group
Stability of X - neutral or stable anions (more electronegative)
make good leaving groups
leaving group I
ability
weak
base
>
H2O
Br
>
>
HO
Cl
>
F
strong
base
5
Alcohols as leaving groups
• Poor leaving group as they react directly with nucleophiles
• Observe deprotonation
R
O
Nu
H
R
• But they are readily converted
• We can protonate them
O
H Nu
to good leaving groups!
SN1
HCl
OH
OH
SN2
H
Cl
OH2
OH
Cl
Ph
H
OH
Br
conc. HBr
H2SO4
Br
Ph
OH2
6
Alcohols as leaving groups II
Alcohols can be converted to good leaving groups with oxophilic
reagents like SOCl2, PCl5, P(O)Cl3 & PBr3
PBr3
OH
Br
O
Br
OH
Br
Br
P
Br
Br
P Br
O
P
Br
Br
Addition of an electron-withdrawing group can make alcohols
good leaving groups
R
OH
O
S
O
Ts = tosyl = toluenesulfonyl
Nu
TsCl
pyr
R
OTs
R
O
Tol
O
S O
O
Nu
Tol
S O
O
Tol
S O
O
O
good leaving group due to delocalisation
7
Ethers as leaving groups
• Normally ethers are stable under most conditions
• They are commonly used as solvents
• But with strong protic acids or Lewis acids they can be cleaved
O
Me
O
OH
HI
SN2
+
+ Et
B = group 3
so empty p
orbital
O
Br
Br
B
O
I
OH
1. BBr3
2. H2O
BBr3
Me
Br
H2O
BBr2
O
Br
Br
8
Epoxides as leaving groups
• Epoxides are excellent electrophiles
• Reason - O & 2 x C are sp3 so bond angles should be 109˚ but are
•
•
forced to be closer to 60˚
The ring is under a lot of strain (ring strain)
This can be released if the epoxide reacts and we get ring opening
OH
O
HNR2
R2N
H
O
HNR2
O
R2N
Why do you think this isomer is formed?
9
Amines as nucleophiles
• Amines are good nucleophiles, readily attacking electrophiles
• But we have a problem (as always)...
H
H
H N
H
R
X
H3N
R
R
H N
R X
H
more nucleophilic
R = electron donating
RH2N
R
H N R
H
R
R N
R X
H
R2HN
even more nucleophilic
R = electron donating
R
R N
R
H N R
H
R N R
H
R
R X
R N R
R
R
H N
H
+
NH4
+
NH3R
+
NH2R2
R
R N
H
R
R N
R
In reality we tend to
produce a mixture!
10
The solution...
• Fortunately there are ways around this problem
• Use "masked" amine - a functional group that is readily converted
•
to an amine
Azide is very good as it is small an will attack most electrophiles
R X +
Na
N N N
R N N N
LiAlH4
reducing agent
R NH2
or...
O
R X + K
N
O
O
R N
O
NH2NH2
hydrolysis
R NH2