Chapter 13 Hydrolysis and Nucleophilic Reactions

1
Chapter 13Hydrolysis and Nucleophilic Reactions
2
Why are nucleophilic reactions important?
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
(negative-loving) Because there are lots of
nucleophiles out there, electrophiles are rapidly
destroyed (except in light-induced or
biologically mediated processes)
Common nucleophiles ClO4- H2O NO3- F- SO42-,
CH3COO- Cl- HCO3-, HPO32- NO2- PhO-, Br-, OH- I-,
CN- HS-, R2NH S2O32-, SO32-, PhS-
3
What are nucleophiles?
ClO4- H2O NO3- F- SO42-, CH3COO- Cl- HCO3-,
HPO32- NO2- PhO-, Br-, OH- I-, CN- HS-,
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
increasing nucleophilicity for reaction at
saturated carbon
4
Example SN2 reaction
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-
5
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.
6
Examples
Unsure about electronegativity? Check the
Periodic Table
7
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
8
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
Note that other nucleophiles may compete with
water here!
9
Another example
CH3COOC2H5 H2O ? CH3COO- HOCH2CH3 H DrGº
19.0 kJ/mol
10
Nucleophilic displacement of halogens at
saturated carbon
The SN2 mechanism substitution, nucleophilic,
bimolecular Note stereochemistry
11
SN2 rate depends on
Nucleophile strength Substrate charge
distribution at the reaction center goodness of
leaving group, steric effects For leaving
groups I Br gt Cl gt F and lowest pKa Rate
law second order kinetics
12
SN1 mechanismsubstitution, nucleophilic,
unimolecular
Note stereochemistry
13
SN1 Mechanism
rate determining step is formation of
carbocation C6H5-CH2Br ? C6H5-CH2
Br- 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
doesnt matter! Rate law first order
14
Swain-Scott model for SN2 reactions
All these methyl halides show the same relative
reactivity towards a series of nucleophiles
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
15
Two references
methyl bromide in water
methyl iodide in methanol
16
the two reference systems yield similar
nucleophilicities
17
Important nucleophiles
some organic nucleophiles are quite strong (NOM
constituents?)
Reduced sulfur species are some of the strongest
nucleophiles in the environment
18
Conc of each nucleophile needed to compete with
water
Nucleophile M conc. NO3- 6 F- 0.6 SO42- 0.2 Cl-
0.06 HCO3-, HPO32- 0.009 Br- 0.007 OH- 0.004 I
- 0.0006 CN- 0.0004 HS- 0.0004 S2O32- 0.00004
S42- 0.000004
Assume s 1
If reaction not acid catalyzed, hydrolysis
independent of pH (4-9) (alkyl halides)
19
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- lt Cl- lt Br- lt I- HO-
lt HS-
20
HSABHard 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-
21
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)
22
Leaving groups
Substituents
Nuc water
SN1 vs SN2 depends on stability of carbocation
AND on strength of nucleophile
23
Fig 13.5
Secondary bromides react via SN1. Will not react
via SN2 with water, but will with reduced sulfur
nucleophiles
24
Polyhalogenated alkanes SN2 blocked
25
SN2 is blocked by steric hindrance and
back-bonding of extra halogens. Why do
tetrachloroethane and pentachloroethane react
relatively rapidly?
26
Elimination mechanisms
CC H L
CC H 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
-kOH-polyhalide
27
Transition state has negative charge on
carbonAnything that can stabilize this charge
will speed up the reaction
steric effects not as important as for SN2
28
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
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
29
Hydrolysis of carboxylic and carbonic acid
derivatives (neutral, acid, or base catalyzed)
Where Z C, P, S X O, S, NR L- RO-,
R1R2N-, RS-, Cl-
Aldicarb (carbamate)
endosulfan
Malathion (organophosphorus pesticide)
Benzyl butyl phthalate
30
(No Transcript)
31
Neutral Mechanism
RLS?
Good leaving groups favor neutral mechanism
32
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?)
33
Base-catalyzed mechanism
RLS with good leaving groups
RLS with poor leaving groups
34
(No Transcript)
35
LFERs for hydrolysis Hammett (aromatic
systems) predicts acid-base equilibrium
Likewise predicts hydrolysis kinetics
36
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)
Where r sensitivity to polar effects s
polar constant d 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?
37
Taft relationship assume that electronic effects
are zero for the acid catalyzed hydrolysis
mechanism
O
OH
R1
OR2
OR2
R1
HO
HO
H
Base catalyzed TS (negative charge)
Acid catalyzed TS (no charge)
38
(No Transcript)
39
Phosphoric and thiophosphoric acid triesters