Nucleophiles, Electrophiles and Leaving Groups Nucleophiles ...

Nucleophiles, Electrophiles and
Leaving Groups
Nucleophiles
• Translation: Nucleus-loving
• Chemical meaning: Reacts with positivelycharged
(or partially positive) atoms
(electrophiles: electron-loving)
• Characteristics: Nucleophilic atoms will
have either lone pairs or pi bonds that can
be used to form new bonds to electrophiles
Nucleophile Examples
Anions
Br
OH C N
H
Pi bonds
H
C
H
H
C
H
H
C C H
H
H
C
C
C
C
C
C
H
H
H
Atoms with lone pairs
H
O
H
H
N
H H
O
C
H 3 C CH 3
1

Relative Nucleophile Strength - Charge
• Given two nucleophiles with the same nucleophilic
atom, a negative charge makes the atom more reactive
OH
is a better nucleophile than
H
O
H
Br
is a better nucleophile than
H
Br
• In more general terms, the stronger base is the stronger
nucleophile (given the same nucleophilic atom)
Relative Nucleophile Strength - Solvent
• Hydrogen-bonding solvents (protic solvents) reduce
nucleophilicity by interacting with the free electrons in
H
the nucleophile
H
O
H
• This effect is particularly strong for small atoms with
concentrated charges, thus larger atoms are more
nucleophilic in protic solvents (~opposite basicity)
HS - > HO -
I - > Br - > Cl - > F -
O
H
N
H H H
O
H
H
O H
H
Relative Nucleophile Strength – Aprotic Solvents
• In solvents that can accept, but not donate
hydrogen bonds, nucleophiles are not solvated
(but the cations providing countercharges are)
• Thus the nucleophilicity and basicity are more
closely correlated:
F - > Cl - > Br - > I -
2

Aprotic Solvent Examples
O
C
H 3 C N CH 3
CH 3
Dimethylacetamide (DMA)
O
C
H N CH 3
CH 3
N,N-Dimethylformamide (DMF)
O
S
H 3 C CH 3
Dimethylsulfoxide
O
(H 3 C) 2 N P
N(CH
(H 3 C) 2 N 3 ) 2
Hexamethylphosphoramide (HMPA)
O
CH 3 CH 2 CH 2 CH 3
diethyl ether
Problem
• Draw a sketch demonstrating how your
assigned solvent from the previous slide can
solvate a cation, and describe why it cannot
solvate an anion
Nucleophilicity vs. Basicity
• Strong nucleophiles tend to be strong bases, but
these properties are not measured the same way
– Base strength is quantitated based on the position of
the equilibrium for that base to accept a proton from
water
– Nucleophile strength is based on relative rates of
reaction with a common electrophile
• Thus basicity is a thermodynamic property and
nucleophilicity is a kinetic property
3

Example
• Example: Hydroxide ion is a stronger base than cyanide ion,
but cyanide ion is a stronger nucleophile (regardless of solvent)
HO - pK a = 15.7
+ H 2 O H 2 O + HO -
NC - + H 2 O HCN + HO -
pK a = 10
HO - +
H
H
C
H
Br
H
H
C
H
OH
NC - +
H
H
C
H
Br
H
H
C
H
CN
faster
Problem
• Rank the following nucleophiles from strongest
to weakest when dissolved in diethyl ether:
Group I: H 2 O HO - H 2 N - H 3 N
Group II: CH 3 Li NaCN CH 2 =CH 2
Electrophiles
• Translation: Electron-loving
• Chemical meaning: Reacts with sources of
electrons (nucleophiles: nucleus-loving)
• Characteristics: Electrophilic atoms will have
– Positive charge, a partial positive charge, or be very
polarizable
– An empty orbital or a heterolytically breakable bond
(to a leaving group)
4

Electrophile Examples
• Charged:
H
H
H
C
H
O
N
O
• Polar:
Br
H
C
H H
δ − δ + O
δ −
C
H 3 C δ + H Cl
CH 3
δ +
δ −
• Polarizable:
Br Br Cl Cl I I
Problem
• Identify all electrophilic or nucleophilic
atoms in the following structure:
Br
O
O
Electrophile Strength - I
• Given the same electrophilic atom, a greater
degree of positive charge gives a stronger
electrophile
H
H
C
H
is a better electrophile than
H
C
Br H H
δ − δ +
O
C
H 3 C CH 3
δ + δ −
is a better electrophile than
OH
C
H 3 C CH 3
δ + δ − CH 3
5

Electrophile Strength - II
• The strength of electrophiles without empty
orbitals (to which a bond must be broken
before another can form) is also influenced
by the nature of the group to which the bond
will be broken (leaving group)
Leaving Groups
• Leaving groups are the fragments that retain
the electrons in a heterolytic bond cleavage:
H
H
C
H H
δ − δ + C
Br
H
+ Br -
H
H
O
H 2 C CH 2
I
O
H 2 C CH 2
I
H
Leaving Group Ability
• Weaker bases are more stable with the extra
pair of electrons and therefore make better
leaving groups
H 2 O > HO -
I - > Br - > Cl - > F -
6

Strategies to Improve Reactivity
• Alcohols do not react easily with nucleophiles
due to the poor leaving ability of hydroxide
• Means to improve reactivity:
– Let oxygen act as base first:
OH
+ H + OH 2
OH
– Let oxygen act as nucleophile first:
O
O
+
H 3 CO S
O
Cl
S 3 S OCH 3
H O OOCH
O O
O
Problem
• Why is the group below a good leaving
group?
O
O
S
OCH 3
O
7