Bringing Light to Dark Reactions:
Acid- and Base Catalysis in Keto–Enol Chemistry
Adv. Phys. Org. Chem., 44, 2010, 325
Many reactions of ketones proceed via their enol tautomers. -> Rates of reaction? Equilibria?
Some Preliminaries
We use water as a solvent: Why?
• over 90% of photochemistry on earth occurs in aqueous solution
• well-defined pH-scale
• heterolytic reactions preferred; no H-abstraction from solvent
• biochemistry is mostly “aqueous”
The definition of pH (IUPAC Gold Book)
Note: pH involves the activity of a single ion, which cannot be measured!
The standard activity of a 1 m solution of H+(aq) at infinite dilution (!!!) is,
therefore, defined as ao = 1.
This looks terribly complicated, but …
In practice: be happy, don’t worry!
Avoid CO2 in air!
Cross-check for buffer solutions
1) H. Sigel, A. D. Zuberbühler, O. Yamauchi, Anal. Chim. Acta, 1991, 255, 63.
Prepare buffer solution as described in the literature (I = 0.1 M)
Measure pH with a glass electrode.
The glass electrode must be calibrated!
(See provider instructions, e.g., Metrohm)
Remarkably, glass electrode readings (pH)meas are closer to
pcH+ than to paH+! 1)
Your results should hold within:
(pH)meas – (pcH+)calc = 0.03 ± 0.02
Interpretation of pH–rate profiles: log(1kobs) = f(pH)
G. M. Loudon, J. Chem. Ed. 1991, 68, 973
(a) 1kobs = kH+cH+ (b) 1kobs = k0
(c) 1kobs = const/cH+
(d) 1kobs = const cH+/(const’ + cH+)
for cH+ << const’: 1kobs = (const/const’) cH+
for cH+ >> const’: 1kobs = const
(e) 1kobs = const/(const’ + cH+)
Downward bends indicate a) the loss or gain of a proton by the substrate or b) a change in the ratelimiting
step with pH. The same mechanism operates to the left and right of negative curvature.
Upward bends indicate a change of mechanism.
Spectrophotometric determination of acidity constants pKa,c
Choose a well-known (preferably monoacid) buffer with
known pKa,c near (±1 unit) to that pKa,c which you want to
determine.
Titrate with 0.1 M strong base starting with 0.1 M HA plus dye or
with 0.1 M strong acid starting with buffer salt plus dye.
Record spectra and get pH readings between small additions of
titrant.
Global analysis (Specfit or Matlab) of the spectral series (number
of components) and fit of an appropriate titration function: Ka,c =
(cA–cH+/cHA).
The thermodynamic acidity constant Ka
o can then be estimated
using known activity coefficients.
pKa,c(3+) = 4.18 ± 0.02, pKa,c(3) = 11.78 ± 0.03; I = 0.1 M
Titration of 2-phenyl-1H-benzimidazole (3)
HOAc/NaOAc No buffer
The mechanisms of keto–enol tautomerization
Enolization and ketonization reactions always observe a first-order rate law, but the observed
rate constants depend on pH.
Assumption:
Protonation equilibria on oxygen are established at all times during keto–enol tautomerization.
e.g., pKa
K = pKE + pKa
E
The primed symbols of rate constants, k‘E and k’K, refer to reactions forming or depleting
The enol anion E–, respectively.
Based on this proposed mechanism we write down the (one-way!) differential rate laws
for ketonization of the enol, vK, and enolization of the ketone, vE, separately:
Acid cat.:
Base cat.:
“Uncat.”:
Three independent rate constants of ketonization, kH+K, k0’K, and kuc
K = k0
K + kH+’KKa
E, fully determine the
kinetic properties of the Scheme, because the rate constants ki
E for the reverse enolization reactions are
related to the former by the principle of microscopic reversibility:
At equilibrium each reaction path is at equilibrium.
Kw = 1.59 x 10–14 M2 at ionic strength I = 0.1 M
Hence, the total enol concentration obeys the first-order rate law for reversible reactions:
pKa
E
Can we measure kE and kK separately?
If KK = cK/cE >> 1, then kobs ~ kK. The reverse rate constant can be measured by, e.g., acid‐
catalyzed bromination:
The rate law is independent of bromine conc.  (Lapworth 1906)
Acetophenone
obs
The bromine titration method
Acetylacetone: 13 %
Acetone: 2.5 x 10–4 %, i.e., pKE = 5.6
In fact (flash photolysis): pKE = 8.3 ± 0.1
Buffer catalysis
The determination of rate constants for a pH‐rate profile in solutions with buffers (pH = 3 –11) 
requires extrapolation to zero buffer concentration.
The determination of the coefficients of general acid catalysis, kHA, and of general base 
catalysis, kA–, requires measurements in buffer solutions with different mole ratios of 
general acid, xHA, and extrapolation to xHA = 0 and 1, respectively.    
k
Photochemical generation of unstable enols and ketones
= –12.7
= 9.8
pKa
K = pKE + pKa
E = –2.9 !!!
Isotopic
exchange
pH–rate profile for 9‐Anthrole –>10H‐Anthr‐9‐one
pKE
Helv. Chim. Acta 2001, 84, 1441
pH-rate profile: o-nitrotoluene
aci-decay
o-Nitrobenzyl methyl ether: pH-profile
hemi decay
cyclo decay
JACS, 2004, 126, 4581
2‐(2,4‐Dinitrobenzyl)pyridine: A light activated proton shuttle
Helv. Chim. Acta, 2009, 92, 1909
pKa,c = 4.18 ± 0.02
Intercepts of buffer dilution plots
pH–Rate profile for the ketonization of phenylynol
pKa(phenylynol) ≤ 2.8 !
Bronsted equation
Bronsted  variation with ∆Go
Marcus theory
Solid line: Marcus eq.
What is the mechanism of the “uncatalyzed” reaction?
Flat portion of pH–rate profile near pH 7 (catalyzed neither by acid nor by base) 
Several mechanisms may be considered:
• Intramolecular 1,5‐H shift in the ketonization of 1,3‐dienols:
• a) water as a general acid
• b) water as a general base
• c) concerted transfer of two protons   
Bronsted eqn: b)
The rate constant of the “uncatalyzed” reaction dominates around pH 7, if ∆rGo >> 0
Is carbon protonation of enols always rate‐determining?
Photochem. Photobiol. Sci.
2012, 11, 967
k0’K = 2x107 s–1
pKa
E = 11.3?
The pKa
E is about 9.6 (from spectrographic flash photolysis in conc. buffer solutions.
Buffer dilution plot
Exercises
1. From the data shown in the pH–rate profile of cyclohexa‐2,4‐dienone, calculate the (CH) acidity 
constant of cyclohexa‐2,4‐dienone.
2. Explain the curvature in the buffer dilution plot of the observed rate constant of ketonization of 2‐
methylacetophenone‐E‐enol.
3. How can you tell that phenylynol ionizes to phenylynolate at all pH‐values ≥ 2.8?  Why is phenynol at 
least 7 orders more acidic than the corresponding enol, PhCH=CHOH, pKa = 9.5?
4. Show that the four proposed mechanisms for the “uncatalyzed ketonization reaction correspond to a 
rate law vK = kuccenol that is independent of acid or base.
5. Discuss the pH–rate profile for the decay of 1‐indene‐2‐carboxylic acid enol.     
Conclusions
• When will YOU do flash photolysis?
• beware of artefacts
• buffer catalysis
• experts in reading pH–rate profiles
• equilibrium constants KE spanning
30 orders magnitude
• assignments of elementary reactions
• LFER