chapter 13 hydrolysis and nucleophilic reactions
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Chapter 13
Hydrolysis and Nucleophilic Reactions
Why are nucleophilic reactions important?
Common nucleophilesClO4
-
H2ONO3
-
F-
SO42-, CH3COO-
Cl-
HCO3-, HPO3
2-
NO2-
PhO-, Br-, OH-
I-, CN-
HS-, R2NHS2O3
2-, 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 (negative-loving)
Because there are lots of nucleophiles out there, electrophiles are rapidly destroyed (except in light-induced or biologically mediated processes)
What are nucleophiles?
ClO4-
H2ONO3
-
F-
SO42-, CH3COO-
Cl-
HCO3-, HPO3
2-
NO2-
PhO-, Br-, OH-
I-, CN-
HS-, R2NHS2O3
2-, SO32-, PhS-
increasing nucleophilicity for reaction at saturated carbon
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-C
H
HH
BrHOC
H
HBr
HC
H
HH
HO+ Br-
-
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-
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.
Hydrolysisbecause 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- rGº = -28.4 kJ/mol
RT
G
BrCH
OHCHHBrK rr exp
][
]][][[
3
3
][
]][10][10[106.9
3
373
4
BrCH
OHCHKr
14
3
3 106.9][
][
BrCH
OHCH Note that other nucleophiles may compete with water here!
Another example
CH3COOC2H5 + H2O CH3COO- + HOCH2CH3 + H+
rGº = +19.0 kJ/mol
4
523
323 107.4][
]][][[
HCOOCCH
CHHOCHCOOCHHK r
3
523
323 107.4][
]][[
HCOOCCH
CHHOCHCOOCH
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
]][[][
33 NuClCHk
dt
ClCHdr
SN1 mechanismsubstitution, nucleophilic, unimolecular
Note stereochemistry
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 doesn’t matter!
Rate law: first order: ])[(])[(
3333 CClCHk
dt
CClCHdr
nsk
k
ref
log
Swain-Scott model for SN2 reactions
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
All these methyl halides show the same relative reactivity towards a series of nucleophiles
Two references:
methyl bromide in water
methyl iodide in methanol
the two reference systems yield similar nucleophilicities
0.98)(R
68.02
,, 33
ICHNuBrCHNu nn
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 M conc.NO3
- 6F- 0.6SO4
2- 0.2Cl- 0.06HCO3
-, HPO32- 0.009
Br- 0.007OH- 0.004I- 0.0006CN- 0.0004HS- 0.0004S2O3
2- 0.00004S4
2- 0.000004
BrCHNunNu 3,103.55][ %50
BrCHNuOH
Nu nsk
k3
2
,log
][][ 2%50 2OHkNuk OHNu
Assume s =1
If reaction not acid catalyzed, hydrolysis independent of pH (4-9) (alkyl halides)
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- < I-
HO- < HS-
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-, SO4
2-, F-, Cl-, NH3, CH3OO
Borderline: H2O, SO32-, Br-, C6H5NH2
Soft: HS-, Sn2-, RS-, PhS-, S2O3
2-, 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)
Leaving groups
SN1 vs SN2 depends on stability of carbocation AND on strength of nucleophile
SubstituentsNuc = water
Fig 13.5
Secondary bromides react via SN1. Will not react via SN2 with water, but will with reduced sulfur nucleophiles
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 LC=C + 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 = -k[OH-][polyhalide]
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
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:
iwj
jNuEBBENN CNukOHkkkkratej
jjNuEBBENNobs NukOHkkkkk
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
Z L
HO-
Z L
HO
X-
Z OH
X
+ L-
Z O-
X
+ HL
Where Z = C, P, S
X = O, S, NR
L- = RO-, R1R2N-, RS-, Cl-
endosulfan Malathion(organophosphorus pesticide)
Aldicarb (carbamate)
Benzyl butyl phthalate
Good leaving groups favor neutral mechanism
RLS?Neutral Mechanism
How strong a base is the ester function? (ie how many molecules are protonated?)
RLS(?)
Important when no electron withdrawing groups and poor leaving group
Acid-catalyzed mechanism
RLS with good leaving groups
RLS with poor leaving groups
Base-catalyzed mechanism
LFERs for hydrolysis: Hammett (aromatic systems):
predicts acid-base equilibrium:
logK
Ka
aHi
i
logk
ka
aHi
i
Likewise predicts hydrolysis kinetics:
C-OCH2CH3
O
X
+ H2O C-OH
O
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)
log * *k
kE
refs
Where * = sensitivity to polar effects * = polar constant = sensitivity to steric effectsEs = 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:
OH
HO
OR2R1
H+
Acid catalyzed TS (no charge)
O
HO
OR2R1
Base catalyzed TS (negative charge)
Phosphoric and thiophosphoric acid triesters
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