Chapter 13
Hydrolysis and Nucleophilic
Reactions
Why are nucleophilic reactions important?
Common nucleophiles
ClO4H2O
NO3FSO42-, CH3COOClHCO3-, HPO32NO2PhO-, Br-, OHI-, CNHS-, R2NH
S2O32-, SO32-, PhS-
Whenever bonds are polarized,
they have permanent dipoles, i.e.
areas of parital positive and
negative charge.
These charges are attractive to
nucleophiles (positive-loving)
and electrophiles (negativeloving)
Because there are lots of
nucleophiles out there,
electrophiles are rapidly
destroyed (except in lightinduced or biologically mediated
processes)
What are nucleophiles?
ClO4H2O
NO3increasing
Fnucleophilicity SO42-, CH3COOfor reaction at ClHCO3-, HPO32saturated
NO2carbon
PhO-, Br-, OHI-, CNHS-, R2NH
S2O32-, SO32-, PhS-
nucleophiles possess
either a negative
charge or lone pair
electrons which are
attracted to partial
positive charges
These electrons
form a new bond at
the carbon they
attack
Example: SN2 reaction
OH-
-
H
H
C
HO
C
H
Br
C
+ Br-
HO
H
H
Br
H H
H
the lone pair electrons on the nucleophile (in
this case OH-) form a new bond with C.
something has to go!
“Leaving Group” in this case is Br-
H
common leaving groups
halides (Cl-, Br-, I-)
alcohol moieties (ROH)
others such as phosphates (PO4-)
anything that forms a stable species in aqueous solution
For negatively charged leaving groups, the lower the pKa,
the better the leaving group.
Examples
Unsure about electronegativity?
Check the Periodic Table
Hydrolysis
because water is so abundant, it is an important nucleophile
reaction where water (or OH) substitutes for a leaving
group is called “hydrolysis”
the products of this reaction are necessarily more polar
Examples:
methyl bromide    methanol
ethyl acetate    acetate and ethanol
Thermodynamics:
at ambient pH, reactant and product concs, most hydrolysis
reactions are spontaneous and irreversible
Example 13.1
CH3Br + H2O  CH3OH + H+ + Br- DrGº = -28.4 kJ/mol
[ Br  ][ H  ][CH 3OH ]
  DrG 
Kr 
 exp 

[CH 3 Br ]
 RT 
3
7
[
10
][
10
][CH 3OH ]
4
K r  9.6 10 
[CH 3 Br ]
[CH 3OH ]
 9.6 1014
[CH 3 Br ]
Note that other nucleophiles
may compete with water here!
Another example
CH3COOC2H5 + H2O  CH3COO- + HOCH2CH3 + H+
DrGº = +19.0 kJ/mol
[ H  ][CH 3COO  ][ HOCH 2CH 3 ]
Kr 
 4.7 104
[CH 3COOC 2 H 5 ]
[CH 3COO  ][ HOCH 2CH 3 ]
 4.7 103
[CH 3COOC 2 H 5 ]
Nucleophilic displacement of
halogens at saturated carbon
The SN2
mechanism:
substitution,
nucleophilic,
bimolecular
Note
stereochemistry
SN2 rate depends on:
Nucleophile: strength
Substrate:
charge distribution at the reaction center
goodness of leaving group,
steric effects
For leaving groups: I ~ Br > Cl > F and lowest pKa
Rate law: second order kinetics
d [CH 3Cl ]
 k r [CH 3Cl ][ Nu  ]
dt
SN1 mechanism
substitution, nucleophilic, unimolecular
Note stereochemistry
SN1 Mechanism:
rate determining step is formation of carbocation:
C H -CH Br  C H -CH + + Br6
5
2
6
5
2
carbocation is then captured by the nearest nucleophile,
almost always water.
Important for {secondary}, tertiary, allyl, benzyl halides
Rate depends on goodness of leaving group and stability of
carbocation (better if resonance stabilized).
Nucleophilicity of nucleophile doesn’t matter!
Rate law: first order:
d [(CH 3 ) 3 CCl ]
 k r [(CH 3 ) 3 CCl ]
dt
Swain-Scott model for SN2 reactions
All these methyl halides show the
same relative reactivity towards a
series of nucleophiles
 k
log 
k
 ref

  sn


k = rate constant for given reaction
k ref = rate constant for same
reaction with reference nucleophile
s = susceptibility of structure to
nucleophilic attack
n = nucleophilicity of nucleophile
Two references:
methyl
bromide
in water
methyl
iodide in
methanol
the two reference systems yield similar
nucleophilicities
nNu ,CH 3Br  0.68nNu ,CH 3I
(R 2  0.98)
Important nucleophiles
some organic
nucleophiles are
quite strong (NOM
constituents?)
Reduced sulfur species are some of
the strongest nucleophiles in the
environment
Conc of each nucleophile needed to
compete with water
Nucleophile
NO3FSO42ClHCO3-, HPO32BrOHICNHSS2O32S42-
M conc.
6
0.6
0.2
0.06
0.009
0.007
0.004
0.0006
0.0004
0.0004
0.00004
0.000004
 k Nu 
  s  nNu ,CH Br
log 
3
 kH O 
 2 
k Nu  [ Nu ]50%  k H 2O  [ H 2O]
If reaction not acid catalyzed, hydrolysis
independent of pH (4-9) (alkyl halides)
Assume s =1
[ Nu]50%  55.3 10
 n Nu ,CH3Br
What factors determine nucleophilicity?
The ease with which it can leave the solvent and
attack the reaction center
(nucleophilicity inc with dec solvation of nuc)
Ability of bonding atom to donate its electrons
(larger, softer species are better nuc)
F- < Cl- < Br- < IHO- < HS-
HSAB
Hard and soft acids and bases
Lewis acids = electrophiles, Lewis bases = nucleophiles
Hard = small, high electronegativity, low polarizability
Soft = large, low electronegativity, high polarizability
Rule 1: Equilibrium: hard acids prefer to associate with hard
bases and soft acids with soft bases.
Rule 2: Kinetics: hard acids react readily with hard bases and
soft acids with soft bases
Hard: OH-, H2PO4-, HOC3-, NO3-, SO42-, F-, Cl-, NH3, CH3OO
Borderline: H2O, SO32-, Br-, C6H5NH2
Soft: HS-, Sn2-, RS-, PhS-, S2O32-, I-, CN-
Range of s
Leaving groups:
0.83-0.96
Hard (oxygen) leaving groups
1-1.2
Softer leaving groups
Substrate properties
1.6
strong interaction with nuc in transition state
(alachlor and propachlor)
Substituents
Nuc = water
Leaving groups
SN1 vs SN2 depends on stability
of carbocation AND on strength
of nucleophile
Secondary
bromides react via
SN1. Will not
react via SN2 with
water, but will
with reduced
sulfur
nucleophiles
Fig 13.5
Polyhalogenated alkanes: SN2 blocked
SN2 is blocked by steric hindrance and back-bonding of extra halogens.
Why do tetrachloroethane and pentachloroethane react relatively
rapidly?
Elimination mechanisms
— C—C —
H
C=C
+ H+ + L-
L
b-elimination
(dehydrohalogenation)
Important for molecules in which multiple halogens block
Sn2 and render the proton acidic
OF COURSE, the molecule must have an acidic proton beta
to a good leaving group (halogen)
1,1,2,2-tetrachloroethane and pentachloroethane undergo an
E2 mechanism (elimination, bimolecular)
OH- base interacts with acidic proton in the transition state
rate = -k[OH-][polyhalide]
Transition state has negative charge on carbon
Anything that can stabilize this charge will speed up
the reaction
steric effects not as
important as for SN2
Summary: For SN and E reactions:
Activation energies are between 80-120 kJ/mol
(big temperature dependence!)
Overall rate of disappearance is the sum of all processes:



rate  k N  k EN  k B  k EB  OH   k Nu j Nu j Ciw
j





kobs  k N  k EN  k B  k EB  OH   k Nu j Nu j 
j




 


 
kobs may not be a simple function pH and T
Products and rates can depend strongly on pH and T
Vinyl and aromatic halides are (for the most part) unreactive by
SN and E mechanisms
Hydrolysis of carboxylic and carbonic acid
derivatives (neutral, acid, or base catalyzed):
X-
X
Z
L
Z
L
HO
HO-
X
X
Z
Z
OH
+ L-
O-
+ HL
Where Z = C, P, S
X = O, S, NR
L- = RO-, R1R2N-, RS-, Cl-
endosulfan
Aldicarb (carbamate)
Malathion
(organophosphorus pesticide)
Benzyl butyl phthalate
Neutral Mechanism
RLS?
Good leaving groups favor neutral mechanism
Acid-catalyzed mechanism
RLS(?)
Important
when no
electron
withdrawing
groups and
poor leaving
group
How strong a
base is the ester
function? (ie
how many
molecules are
protonated?)
Base-catalyzed mechanism
RLS with good
leaving groups
RLS
with
poor
leaving
groups
LFERs for hydrolysis:
Hammett (aromatic systems):
predicts acid-base equilibrium:
 Ka 
log
   i
 KaH 
i
Likewise predicts hydrolysis kinetics:
 ka 
log
   i
 kaH 
i
O
C-OCH2CH3
X
O
+ H2O 
C-OH
X
+ HOCH2CH3
Taft relationship (aliphatic systems):
commonly applied to ester hydrolysis of aliphatic systems (reactivity only)
quantifies steric and polar effects
defined for methyl substituent (methyl = 0)
 k
log
 k ref

   *  * E s

Where
* = sensitivity to polar effects
* = polar constant
 = sensitivity to steric effects
Es = steric constant
Assume only steric effects are important for acid-catalyzed hydrolysis.
Both steric and polar effects are important for base-catalyzed hydrolysis.
What does the transition state look like?
Does it possess positive or negative charge?
Taft relationship:
assume that electronic effects are zero for the acid catalyzed
hydrolysis mechanism:
O
OH
R1
OR2
HO
H+
Acid catalyzed TS
(no charge)
R1
OR2
HO
Base catalyzed TS
(negative charge)
Phosphoric and
thiophosphoric
acid triesters