Aryl Trifluoroacetate Hydrolysis

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Aryl Trifluoroacetate Hydrolysis

• Aim to determine mechanism of

Fernandez and de Rossi. J. Org. Chem. 1999, 64,
6000.
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Basic Ester Hydrolysis
Importance biological, industrial
saponification, flavorings Mechanism
rds
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Free Energy
Standard Energy Diagram
energy
tetrahedral intermediate
reaction coordinate
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Reaction Coordinate

• What exactly is it? Consider SN2
• Consider rxn coordinate as having two components
• Extent of bond breaking
• Extent of bond formation

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Another Representation
Instead of a single axis reaction coordinate, use
two
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Ester Hydrolysis
C-O bond formation
leaving group rupture
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Jencks-More OFerral Diagram
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Aryl Trifluoroacetates?
Predict CF3 EWG stabilizes tetrahedral
intermediate and destabilizes acylium ion
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• End of Story?
• Authors carried rxns
• Experimental
• Reaction 25.0C, constant ionic strength 0.2 M
  (made up with NaCl), pH 5-10 (pH meter),
  solvent MeCN/water.
• Kinetic Unequal mixing stopped-flow, phenol
  monitored at 280 nm.
• Synthesis Phenol TFA anhydride.
• Solvent KIE Buffers made up in D2O

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• Results I
• Kinetics kobs kwater khydroxideOH
  kbasebase
• pH Rate Profile k kwater kbasebase
• (2) Solvent KIE (kH/kD)
• kwater 2.5 (probably involved in rds)
• kbase no apparent trend (0.2-2)
• khydroxide inverse (0.4-0.8) (desolvation)

log k
Implies general base catalysis!
Water in rds?
pH saturation effect
pKaBH pH
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Results II (3) Hammett log kbase rs, rs- (a)
Much better fit to s rather than s-. No acylium
ion? Problem groups tried have small
difference between s and s-. P-NO2 tried, but
rxn too fast. Possible Solution para-aldehyde
like 4-formyl? (b) r is positive and increases
with increasing basicity Negative charge in
rate-determining TS. (c) magnitude of r 1.3
(acetate), 2.0 (hydrogen phosphate), 3.0
(carbonate) Cant tell much at all.
X H, p-Me, p-F, p-Cl, m-Cl
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Conclusion Authors propose

• general base catalyzed nucleophilic addition of
  water
• no intermediate of detectable lifetime, i.e., no
  tetrahedral intermediate
• Hammett r increases with increasing basicity of
  B
• strong base earlier proton transfer, more
  negative
• charge near ring in T.S., more sensitive to
  electronic effects, higher r

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Proposed Mechanism
tetrahedral character r gt 0
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Criticisms 1. Hammett Not enough
substituents. 2. Possible spectroscopic study?
-ATR FTIR allows reactions to be monitored
in solution - CO bond would change to
a C-O bond if a tetrahedral intermediate was
present
1700-1750 cm-1
1200 cm-1
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Another Proposed Experiment Isotopic
Labelling - known for aliphatic
esters Observe Amount of oxygen-18
severely reduced.
Bender. JACS, 1951, 73(4), 1626.
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Proposed Experiments Isotopic Labelling -
explanation - if tetrahedral
intermediate, should see similar exchange - if
present, would need to confirm it can produce
products