Flash photolytic generation of ?-quinone α-phenylmethide and ?-quinone α-(p-anisyl)methide in queous solution and investigation of their reactions in that medium. Saturation of acid-catalyzed hydration

Article abstract of DOI:10.1021/ja0120375

?-Quinone α-phenylmethide was generated as a short-lived transient species in aqueous solution by flash photolysis of ?-hydroxy-α-phenylbenzyl alcohol, and its rate of decay was measured in HCIO₄ and NaOH solutions as well as in CH₃C

Full text of DOI:10.1021/ja0120375

Published on Web 12/29/2001
Flash Photolytic Generation of o-Quinone r-Phenylmethide
and o-Quinone r-(p-Anisyl)methide in Aqueous Solution and
Investigation of Their Reactions in that Medium. Saturation of
Acid-Catalyzed Hydration
Y. Chiang, A. J. Kresge,* and Y. Zhu
Contribution from the Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario M5S 3H6, Canada
Received August 23, 2001. Revised Manuscript Received November 5, 2001
Abstract: o-Quinone R-phenylmethide was generated as a short-lived transient species in aqueous solution
by flash photolysis of o-hydroxy-R-phenylbenzyl alcohol, and its rate of decay was measured in HClO4 and
-
NaOH solutions as well as in CH3CO2H, H2PO4-, and HCO3 buffers. These data show that hydration of
this quinone methide back to its benzyl alcohol precursor occurs by acid-, base-, and uncatalyzed routes.
+
+
The acid-catalyzed reaction gives the solvent isotope effect kH /kD ) 0.34, whose inverse nature indicates
that this reaction occurs via rapid preequilibrium protonation of the quinone methide on its carbonyl oxygen
atom followed by rate-determining capture of the ensuing carbocationic intermediate by water, a conclusion
supported by the saturation of acid catalysis in concentrated HClO4 solution. o-Quinone R-(p-anisyl)methide
was also generated by flash photolysis of the corresponding benzyl alcohol and of the p-cyanophenol
ether of this alcohol as well, and its rate of decay was measured in HClO4 and NaOH solutions and in
HCO2H, CH3CO2H, HN3, CF3CH2NH3+, imidazolium ion, H2PO4-, (CH2OH)3CNH3+, (CH3)3CPO3H-, and
-
HCO3 buffers. Acid-, base-, and uncatalyzed hydration reaction routes were again found, and solvent
isotope effects as well as saturation of acid catalysis, this time in dilute HClO4, confirmed a preequilibrium
mechanism for the acid-catalyzed reaction. Analysis of the buffer data gave buffer-base rate constants
that did not conform to the Brønsted relation, consistent with the expected nucleophilic nature of the buffer
reactions.
Quinone methides are interesting reactive species with both
electrophilic and nucleophilic properties that make them useful
synthetic intermediates.1 They also show pronounced biological
activity and have been implicated as the ultimate cytotoxins
responsible for the effects of such agents as antitumor drugs,
antibiotics, and DNA alkylators.2
We recently showed that the parent substance, o-quinone
methide, 1, undergoes hydronium-ion catalyzed hydration in
aqueous solution by a reaction mechanism that involves rapid
equilibrium protonation of the substrate on its carbonyl oxygen
atom followed by rate-determining nucleophilic capture of the
ensuing carbocation, 2, by water, eq 1.3 In sufficiently strong
unable to achieve such saturation with o-quinone methide itself,
but we have now found saturation of acid catalysis with the
more basic substrates o-quinone R-phenylmethide, 3, and
o-quinone R-(p-anisyl)methide, 4. The additional phenyl group
in 3, and especially the p-anisyl group in 4, stabilize the
carbocationic intermediate of this reaction mechanism and cause
saturation of hydronium-ion catalysis to occur in an accessible
acidity region.
We generated these quinone methides by photodehydration
of the corresponding o-hydroxybenzyl alcohols, 5 and 6; this
is a well-known quinone methide forming reaction.4 We also
obtained 4 by photocleavage of the o-hydroxybenzyl p-cy-
anophenyl ether 7. Because the reactions of these quinone
methides were fast, we used flash photolytic techniques to
monitor their progress.
acidic solutions, the position of this protonation equilibrium
should shift from unprotonated to protonated quinone methide,
and acid catalysis should then become saturated. We were
Experimental Section
(1) For a brief review, see: Wan, P.; Barker, B.; Diao, L.; Fischer, M.; Shi,
Y.; Yang, C. Can. J. Chem. 1996, 74, 465-475.
Materials. o-Hydroxy-R-phenylbenzyl alcohol (5) was prepared by
treating salicylaldehyde with phenylmagnesium bromide,5 and o-hy-
droxy-R-(p-anisyl)benzyl alcohol (6) was prepared by a similar reaction
(2) See for example: Peter, M. G. Angew. Chem., Int. Ed. Engl. 1989, 28,
555-570. Bolton, J. L.; Pisha, E.; Zhang, F.; Qiu, S. Chem. Res. Toxicol.
1998, 11, 1113-1117. Pande, P.; Shearer, J.; Yang, J.; Greenberg, W. A.;
Rokita, S. E. J. Am. Chem. Soc. 1999, 121, 6773-6779.
(3) (a) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2000, 122, 9854-
9855; (b) 2001, 123, 8089-8094.
(4) Diao, L.; Yang, C.; Wan, P. J. Am. Chem. Soc. 1995, 117, 5369-5370.
9
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J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002 717

A R T I C L E S
Chiang et al.
using p-anisylmagnesium bromide. The latter alcohol was characterized
by its NMR and mass spectra. 1H NMR (200 MHz, CDCl3): δ/ppm )
8.14 (s, 1H), 7.29-6.78 (m, 8H), 5.91 (s, 1H), 3.77 (s, 3H), 3.26 (s,
1H). 13C NMR (50 MHz, CDCl3): δ/ppm ) 160.0, 156.0, 134.7, 129.7,
128.8, 128.7, 127.3, 120.4, 117.7, 114.6, 77.1, 55.8. HRMS: m/e )
229.0865 (calc), 229.0855 (found).
o-Hydroxy-R-(p-anisyl)benzyl p-cyanophenol ether (7) was prepared
by the one-pot process developed for the synthesis of the parent
o-hydroxybenzyl p-cyanophenol ether,3b which involved first converting
o-hydroxy-R-(p-anisyl)benzyl alcohol to the corresponding bromide,
using the mild conditions of the Ph3P/CBr4 reagent,6 and then
immediately adding sodium p-cyanophenoxide. The product was
purified by chromatography on silica gel with hexane and then hexane/
diethyl ether (100/5) as the eluent. This gave a colorless liquid in 75%
1
yield. H NMR (200 MHz, CDCl3): δ/ppm ) 7.51 (d, J ) 8.6 Hz,
2H), 7.30 (d, J ) 8.6 Hz, 2H), 7.15 (m, 1H), 6.88 (m, 7H), 5.96 (s,
1H), 3.77 (s, 3H). HRMS: m/e ) 331.1208 (calc), 331.1193 (found).
All other materials were best available commercial grades.
Figure 1. Rate profile for the hydration of o-quinone R-phenylmethide in
aqueous solution at 25 °C.
Kinetics. Rate measurements were made using microsecond7 and
nanosecond8 (λexc ) 248 nm) flash photolysis systems that have already
been described.7,8 Substrate concentrations in the reacting solutions were
ca. 10-4 M, and the temperature of these solutions was controlled at
25.0 ( 0.05 °C. Reactions were monitored by following the decay of
quinone methide absorbance at λ ) ca. 400 nm. Observed first-order
rate constants were calculated by least-squares fitting of a single-
exponential function; in some cases, however, instrumental instability
caused minor baseline drift, and a linear term was then added to the
exponential fitting function.
The rate measurements in buffers were made in series of
solutions of constant buffer ratio, and therefore constant
hydronium ion concentration, but varying total buffer concentra-
tion. Observed first-order rate constants increased linearly with
increasing buffer concentration, and the data were therefore
analyzed by least-squares fitting of the buffer dilution expression
shown in eq 2. The buffer-independent intercepts, ko, obtained
in this way were then combined with the rate constants
Results and Discussion
kobs ) ko + kbuff[Buffer]
(2)
o-Quinone r-Phenylmethide. Rates of decay of o-quinone
R-phenylmethide were measured in dilute solutions of perchloric
acid in H2O and in D2O, in dilute solutions of sodium hydroxide
in H2O, and in dilute acetic acid, biphosphate ion, and
bicarbonate ion buffers, also in H2O. The ionic strength of the
reacting solutions was maintained at 0.10 M by adding sodium
perchlorate as required, and their temperature during rate
measurements was maintained at 25.0 ( 0.05 °C. The data thus
obtained are summarized in Tables S1-S3.9
determined in the perchloric acid and sodium hydroxide
solutions to construct the rate profile shown in Figure 1.
Hydronium ion concentrations of the buffer solutions needed
for this purpose were obtained by calculation, using literature
pKa values of the buffer acids and activity coefficients recom-
mended by Bates.12
This rate profile shows both acid- and base-catalyzed limbs
as well as a central uncatalyzed portion. It therefore conforms
to the simple rate law shown in eq 3, and least-squares fitting
Observed first-order rate constants determined in these
perchloric acid solutions increased linearly with increasing acid
concentration, and the data were therefore subjected to linear
kobs ) kH+[H+] + k + k -[HO-]
(3)
uc
HO
least-squares analysis. This gave the hydronium ion rate constant
+
6
of this expression gave kH ) (1.18 ( 0.02) × 106 M-1 s-1
,
kH ) (1.22 ( 0.02) × 10 M-1 s-1 and the isotope effect kH
/
+
+
kuc ) 2.43 ( 0.17 s-1, and kHO ) (4.71 ( 0.20) × 102 M-1
-
+
kD ) 0.338 ( 0.006. The inverse nature of this isotope effect
(kH/kD < 1) provides evidence that this reaction occurs by the
preequilibrium mechanism shown in eq 1.10 This follows from
the fact that the positively charged O-H bonds of the hydronium
ion are looser than the uncharged O-H bonds of the water
molecule formed in the preequilibrium step; the reaction
therefore proceeds with a tightening up of the hydrogenic
environment, and that makes the isotope effect inverse.11
s-1
.
The rate of o-quinone R-phenylmethide decay was found to
be strongly accelerated by thiocyanate ion in a process that was
also acid-catalyzed. This reaction may be formulated as an
analogue, eq 4, of that shown in eq 1, in which the much more
nucleophilic thiocyanate ion takes the place of a water molecule.
(5) Becker, H.-D.; Bremholt, T. Tetrahedron Lett. 1973, 197-200.
(6) Wagner, A.; Heitz, M.-P.; Moskowski, C. Tetrahedron Lett. 1989, 30, 557-
558. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811.
(7) Chiang, Y.; Hojatti, M.; Keeffe, J. R.; Kresge, A. J.; Schepp, N. P.; Wirz,
J. J. Am. Chem. Soc. 1987, 109, 4000-4009.
Rates of this reaction were measured in series of aqueous (H2O)
solutions of constant perchloric acid concentration but varying
sodium thiocyanate concentration. The data thus obtained are
summarized in Table S4.9
(8) Andraos, J.; Chiang, Y.; Huang, C. G.; Kresge, A. J.; Scaiano, J. C. J. Am.
Chem. Soc. 1993, 115, 10605-10610.
(9) Supporting Information; see paragraph at the end of this paper regarding
availability.
(10) Keeffe, J. R.; Kresge, A. J. In InVestigation of Rates and Mechanisms of
Reactions; Bernasconi, C. F., Ed.; Wiley: New York, 1986; pp 761-766.
(11) Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F. In Isotopes in Organic
Chemistry; Buncel, E., Lee, C. C., Eds.; Elsevier: New York, 1987; Vol.
7, pp 220-226.
(12) Bates, R. G. Determination of pH Theory and Practice; Wiley: New York,
1973; p 49.
9
718 J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002

Photolytic Generation of o-Quinone R-Phenylmethide
A R T I C L E S
Observed first-order rate constants measured in these solutions
increased linearly with increasing thiocyanate ion concentration,
and the data were therefore subjected to linear least-squares
analysis. The ∆kobs/∆[SCN-] gradients obtained in this way also
increased linearly with increasing perchloric acid concentration,
and further linear least-squares analysis produced the relationship
∆kobs/∆[SCN-] ) (3.00 ( 0.28) × 105 + (1.06 ( 0.10) × 109
[HClO4]. The nonacid-catalyzed intercept of this relationship
is the rate constant, kN, for reaction of thiocyanate ion with
unprotonated quinone methide, and the coefficient of [HClO4]
is the rate constant, k′N/KSH, for reaction of thiocyanate ion with
the protonated quinone methide through the o-hydroxydiphen-
ylmethyl cationic intermediate, 8, of eq 4.
It is likely that the cation-capture step of eq 4, with rate
constant k′N, is an encounter-controlled process. This follows
from the fact that the capture of the p-methoxydiphenylmethyl
cation, 9, whose reactivity toward nucleophiles may be expected
to be similar to that of o-hydroxydiphenylmethyl cation, 8, by
azide ion, whose strength as a nucleophile is less than that of
the thiocyanate ion used here,13 is an encounter-controlled
process.14 Giving k′N the encounter-controlled value of 5 × 109
Figure 2. Comparison of rate constants for the hydration of o-quinone
R-phenylmethide measured in dilute (O) and concentrated (∆) perchloric
acid solutions at 25 °C.
Quantitative analysis of these data obtained in concentrated
perchloric acid is complicated by the need to use acidity
functions to represent the acid strength of the concentrated
solutions employed. To avoid this complication, we turned to
the more basic substrate o-quinone R-(p-anisyl)methide, whose
acid-catalyzed hydration becomes saturated in dilute solution
where acidity function treatments need not be employed.
o-Quinone r-(p-Anisyl)methide. Rates of decay of o-qui-
none R-(p-anisyl)methide were measured in dilute perchloric
acid solutions in H2O and in D2O, in dilute sodium hydroxide
solutions in H2O and in formic acid, hydrazoic acid, acetic acid,
trifluorethylammonium ion, imidazolium ion, biphosphate ion,
tris-(hydroxymethyl)methylammonium ion, tert-butylhydrogen
phosphonium ion, and bicarbonate ion buffers, all in H2O. The
ionic strength of the sodium hydroxide and buffer solutions, as
well as the perchloric acid solutions up to an acid concentration
of 0.10 M, was maintained at 0.10 M, whereas those of the
perchloric acid solutions above 0.10 M (up to 0.37 M in H2O
and 0.29 M in D2O) were equal to the acid concentration. All
of the rate measurements were made at 25.0 ( 0.05 °C. The
data thus obtained are summarized in Tables S6-S8.9
M-1 s-1 in the expression k′N/KSH ) (1.06) × 109 M-2 s-1 then
leads to KSH ) 4.7 M, pKSH ) -0.67, as an estimate of the
acidity constant of carbonyl-oxygen protonated o-quinone
R-phenylmethide.
This estimate of KSH may be combined with the rate constant
6
kH () 1.18 × 10 M-1 s-1; vide supra) of the simple rate law
of eq 3, which in terms of the mechanism of eq 1 is equal to
k′w/KSH, to give k′w ) 5.6 × 106 s-1 as the rate constant for
capture of the o-hydroxydiphenylmethyl cation, 8, by water.
This result is consistent with k ) 2 × 106 s-1 determined for
the capture by water of the p-methoxydiphenylmethyl cation,
9,14,15 which is the closest analogue to the present system for
which such a rate constant has been reported.
+
Some measurements of the rate of o-quinone R-phenylmethide
decay were also made in concentrated perchloric acid solutions
over the concentration range [HClO4] ) 0.23-3.7 M at variable
ionic strengths equal to the acid concentrations. These data are
summarized in Table S59 and are displayed in Figure 2.
This figure shows that acid catalysis of this reaction levels
off and becomes saturated at [HClO4] ) ca. 2.5 M. Such
saturation is, of course, as expected for the preequilibrium
reaction mechanism of eq 1, and it provides strong additional
support for this reaction scheme. Figure 2 also shows that above
[HClO4] ) ca. 2.5 M, rate constants begin to drop. This, also,
is consistent with expectation, for perchlorate ion is known to
inhibit the rate of reaction of large delocalized carbocations with
water, an effect that has been attributed to carbocation-
perchlorate ion ion-pair formation.16
Most of these rate measurements were made using o-hydroxy-
R-(p-anisyl)benzyl alcohol as the flash photolysis substrate, but
in some of the perchloric acid solutions o-hydroxy-R-(p-anisyl)-
benzyl p-cyanophenyl ether was used as well. Exactly equivalent
results were obtained with the two substrates.
The rate measurements in buffers were again made in series
of solutions of constant buffer ratio, and therefore constant
hydronium ion concentration, but varying buffer concentration,
and the data were again analyzed by least-squares fitting of eq
2. Buffer catalysis was very strong in the hydrazoic acid,
trifluoroethylammonium ion, and imidazolium ion buffers, and
the buffer-independent intercepts, ko, of the buffer dilution plots
for these buffers were consequently very small and poorly
defined; they were therefore not used for rate profile construc-
tion. The intercepts of the other buffer solutions, however, were
well determined, and they were therefore combined with the
perchloric acid and sodium hydroxide data to give the rate
profile shown in Figure 3.
(13) Swain, C. G.; Scott, C. B. J. Am. Chem. Soc. 1953, 75, 141-147. Pearson,
R. G. In AdVances in Linear Free Energy Relationships; Chapman, N. B.,
Shorter, J., Eds.; Plenum: New York, 1972; Chapter 6.
(14) McClelland, R. A.; Kanagasabapathy, V. M.; Steenken, S. J. Am. Chem.
Soc. 1988, 110, 6913-6914.
(15) McClelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.; Steenken, S.
J. Am. Chem. Soc. 1989, 111, 3966-3972.
(16) See: (a) Crugeiras, J.; Maskill, H. Can. J. Chem. 1999, 77, 530-536; (b)
J. Chem. Soc., Perkin Trans. 2 2000, 441-445 and references therein.
9
J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002 719

A R T I C L E S
Chiang et al.
Figure 3. Rate profile for the hydration of o-quinone R-(p-anisyl)methide
in dilute aqueous solution at 25 °C.
Figure 4. Comparison of rates of hydration of o-quinone R-(p-anisyl)-
methide in H2O (O) and D2O (∆) solutions of perchloric acid at 25 °C.
This figure shows that saturation of acid catalysis for reaction
of this substrate occurs in the dilute acid region just above
[HClO4] ) 0.1 M; the data may therefore be analyzed without
recourse to an acidity function. Saturation of acid catalysis
implies, of course, that the preequilibrium reaction mechanism
of eq 1 is operating, but this scheme must now be modified to
include reduction of the concentration of the reactive carbocation
intermediate by ion pair formation, as shown in eq 5.
that makes these substances much stronger bases and their
conjugate acids correspondingly less acidic.
Additional support for a preequilibrium reaction mechanism
comes from the solvent isotope effects provided by the rate
measurements made in D2O solutions of perchloric acid. These
rate measurements are compared with their H2O counterparts
in Figure 4. It may be seen that at low acidities the reaction is
faster in D2O than in H2O which gives an inverse isotope effect,
+
+
kH /kD ) 0.351 ( 0.013, that is characteristic of a preequilib-
rium mechanism. At higher acidities, however, saturation of acid
catalysis occurs earlier in D2O than in H2O, and a crossover
takes place, with the reaction becoming slightly faster in H2O
than in D2O at the highest acidities investigated. Quantitative
analysis of the data using the first term only of the rate law of
eq 6 gives the isotope effects KSH/KSD ) 3.49 ( 0.10, (k′w)H O
/
2
(k′w)D O ) 1.22 ( 0.03, and (K1P)H O/(K1P)D O ) 1.44 ( 0.30.
2
2
2
The simple rate law of eq 3 must also be modified to include
an ion-pair formation constant, KIP, as well as explicit inclusion
of the acidity constant of the O-H bond of the carbocation
intermediate, KSH, and the rate constant for reaction of this
intermediate with water, k′w. The result is shown as eq 6. Least-
squares fitting of this expression gave k′w ) (5.22 ( 0.30) ×
105 s-1, KSH ) (1.09 ( 0.07) × 10-1 M, KIP ) (1.69 ( 0.35)
M-1, kuc ) (3.03 ( 0.07) s-1, and kHO- ) (4.82 ( 0.11) × 102
M-1 s-1. The value of k′w obtained is consistent with k )
1.3 × 105 s-1 for the reaction of the di-(p-anisyl)methyl cation
The first of these results is a typical value for the equilibrium
ionization of an oxygen acid;18 the solvent isotope effect on
the ionization of acetic acid, for example, is KH/KD ) 3.3.19
Such isotope effects are produced by the conversion of the
relatively tight uncharged O-H bonds of the acid and a water
molecule into the somewhat looser, positively charged O-H
bonds of a hydronium ion. The isotope effect on k′w, the rate
constant for capture of the carbocation intermediate by a water
molecule, is also as expected, for the capturing water molecule
in this process is taking on positive charge, and its O-H bonds
are consequently being loosened; this loosening, however, is
only slightly developed in the early transition state of this quite
fast reaction, and the magnitude of this isotope effect is small.
The isotope effect on the ion-pair formation constant, KIP, is
essentially unity, and that is also consistent with the nature of
this process, which requires only some rearrangement of the
solvent shells of the ions involved without large changes in
solvent O-H bond strength; isotope effects on solvation shells
are known to be small.20
k′W[H+]
KSH + [H+](1 + KIP[H+])
kobs
)
+ kuc + kHO-[HO-] (6)
with water,15 which is the closest analogue of the present system
for which such a rate constant has been reported, and the value
of KIP obtained here agrees well with KIP ) 1.45 M-1
determined for ion pair formation between perchlorate ion and
the di-(p-anisyl)phenylmethyl cation.16a The value obtained for
the acidity constant KSH, as well as pKSH ) -0.67 estimated
above for o-quinone R-phenylmethide, however, make these
carbonyl-oxygen protonated quinone methides much weaker
acids than carbonyl-protonated simple ketones,17 but protonation
of the quinone methides generates an aromatic phenol ring, and
Some measurements of the decay of o-quinone R-(p-anisyl)-
methide in aqueous (H2O) thiocyanate ion solutions at fixed
(18) Laughton, P. M.; Robertson, R. E. In Solute-SolVent Interactions; Coetzee,
J. F., Ritchie, C. D., Eds.; Dekker: New York, 1969; Chapter 7.
(19) Gary, R.; Bates, R. G.; Robinson, R. A. J. Phys. Chem. 1965, 69, 2750-
2753. Gold, V.; Lowe, B. M. J. Chem. Soc. A 1968, 1923-1932.
(20) Albery, W. J. In Proton-Transfer Reactions; Caldin, E. F., Gold, V., Eds.;
Chapman and Hall: London, 1975; pp 282-283.
(17) Bagno, A.; Scorrano, G.; More O’Ferrall, R. A. ReV. Chem. Intermed. 1987,
7, 313-352.
9
720 J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002

Photolytic Generation of o-Quinone R-Phenylmethide
A R T I C L E S
Table 1. Rate Constants for the Reaction of o-Quinone
R-(p-Anisyl)methide and Its Conjugate Acid with Nucleophiles in
Aqueous Solution at 25 °C
nucleophile
pK (HNuc)
a
kN/M-1 s-1a
k′N/M-1 s-1b
H2O
-1.74
-1.28
3.75
4.65
4.76
5.59
6.99
7.20
8.07
0.0546
9410
SCN-
HCO2
1.64 × 109
3.58 × 106
9.97 × 108
3.84 × 106
2.64 × 107
2.52 × 107
7.96 × 106
6.86 × 108
5.14 × 107
7.93 × 109
-
N3
1.35 × 106
-
-
CH3CO2
CF3CH2NH2
imidazole
HPO4
(CH2OH)3CNH2
4740
833
8.37
851
11.0
86.4
2-
2-
(CH3)3CPO3
8.71
10.33
2-
CO3
a Rate constant for reaction of the unprotonated quinone methide. b Rate
constant for reaction of the protonated quinone methide.
Figure 5. Rate profile for the reaction of o-quinone R-(p-anisyl)methide
with thiocyanate ion in aqueous (H2O) perchloric acid solutions at 25 °C.
perchloric acid concentrations were also made. These data are
summarized in Table S9.9 Observed first-order rate constants
determined at constant acidity increased linearly with increasing
thiocyanate ion concentration, and the data were therefore
subjected to linear least-squares analysis. The second-order
thiocyanate ion rate constants obtained in this way are displayed
in Figure 5.21
This figure shows that the thiocyanate reaction is acid-
catalyzed at low acid concentrations but that this catalysis
becomes saturated at higher acidities. This behavior is similar
to that of the hydration reaction (see Figure 4) and implies that
this reaction also occurs by a preequilibrium mechanism
involving rapid protonation of the quinone methide followed
by thiocyanate capture of the carbocation thus formed. The data
were therefore analyzed by an analogue of the method used for
acid-catalyzed hydration, by least-squares fitting of the first term
of the rate expression of eq 6 with k′SCN substituted for k′w.
Figure 6. Brønsted type plots for the reaction of nucleophiles with
o-quinone R-(p-anisyl)methide (∆) and its conjugate acid (O) in aqueous
solution at 25 °C.
in Table 1. The scheme of eq 8 also leads to the further
relationship kHA ) k′NKaHA/KSH, from which k′N may be
evaluated using the known values of KaHA, the acidity constant
of the buffer acid, and KSH, the acidity constant of the protonated
quinone methide. Values of k′N obtained in this way are also
listed in Table 1.
This gave the results k′SCN ) (1.64 ( 0.99) × 109 M-1 s-1
,
KSH ) (6.55 ( 0.47) × 10-2 M, and KIP ) (8.13 ( 4.07) ×
10-1 M-1. These values of KSH and KIP are consistent with the
results obtained by analysis of the hydration reaction rate profile
(vide supra); the weighted average of the two sets of results
gives KSH ) (7.78 ( 0.40) × 10-2 M, pKa ) 1.11 ( 0.02, and
KIP ) 1.32 ( 0.27 M-1 as the best values of these constants.
Analysis of the rate data for decay of o-quinone R-(p-anisyl)-
methide in buffer solutions using eq 2 produced rate constants
for reaction through the buffer species, kbuff, in addition to the
zero-buffer concentration intercepts, ko. These buffer rate
constants were separated into their buffer acid, kHA, and buffer
base, kB, components by least-squares fitting of eq 7, in which
fA is the fraction of buffer present in the acid form.
Justification for formulating the buffer processes as nucleo-
philic reactions of the buffer bases comes from the poor
Brønsted relations that the data give. It is well known that basic
strength is only one of the factors that governs nucleophilic
reactivity,23 and nucleophilic reactions of bases of such widely
different types as the present set give notoriously poor Brønsted
plots.24 Figure 6 shows that this is easily the case for the present
data; both kN and k′N give plots that are essentially scatter
diagrams, with undefined Brønsted exponents, â ) 0.17 ( 0.25
kbuff ) kB + (kHA - kB)fA
(7)
These buffer reactions may be formulated as shown in eq 8,
where the unprotonated and protonated quinone methides react
with the buffer base acting as a nucleophile, with rate constants
kN and k′N, respectively. This formulation leads to the relation-
ship kB ) kN, and values of kN obtained in this way are listed
(21) Minor corrections for small extents of conversion of thiocyanate ion to its
unreactive protonated form at the highest acid concentrations employed
were made using the recently determined ionization constant of isothio-
cyanic acid, pKa ) -1.28.22
(22) Chiang, Y.; Kresge, A. J. Can. J. Chem. 2000, 78, 1627-1628.
(23) See for example: Jencks, W. P. Catalysis in Chemistry and Enzymology;
McGraw-Hill: New York, 1969; pp 78-111.
(24) Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 1778-1786.
9
J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002 721

A R T I C L E S
Chiang et al.
Table 2. Comparison of Quinone Methide Reactivitya
Mechanism of the Quinone Methide Generating Photo-
reaction. It has been reported1,4 that the transient absorbance
signal given by o-quinone R-phenylmethide, generated by flash
photolysis of o-hydroxy-R-phenylbenzyl alcohol in aqueous
solution, decreased in intensity with increasing solvent acidity
until it was lost completely below pH ) 1. A plot of this signal
intensity versus pH, moreover, was found to be sigmoid in shape
with an inflection point at pH ) ca. 2.5. On the basis of this,
a mechanism for the photoreaction was proposed that involved
excitation of the benzyl alcohol photochemical substrate fol-
lowed by ionization of its phenolic group, whose excited-state
pKa was judged to be ca. 2.5. Suppression of this requisite
excited-state ionization at low pH was then taken to be the
reason for signal loss.
Our observation of continuing acid-catalyzed hydration of
o-quinone R-phenylmethide well up into the concentrated acid
region is at variance with this earlier report. In a series of flash
photolysis experiments, moreover, in which we took care to
keep the laser power and the concentration of the o-hydroxy-
R-phenylbenzyl alcohol photochemical substrate constant, we
observed much the same initial intensity of the transient signal
over the acidity range neutral solution to 1 M perchloric acid.
We suspect that the source of this difference between the
previous and the present studies is the failure by the previous
investigators to recognize that the hydration reaction is acid-
catalyzed. They could then quite easily have used a time frame
throughout their work that was appropriate for the quite slow
reaction at neutral pH but too slow to catch all of the much
faster reactions at acidic pH’s. The evidence requiring a reaction
mechanism involving quinone methide generation via excited-
state phenolic group ionization should therefore be discounted.
substrate
kH+/M-1 s-1
pKSH/M
-1.72
k′w/s-1
8.4 × 10-5
4.4 × 107
1.18 × 106
-0.67
5.6 × 106
6.7 × 106
1.11
5.2 × 105
a
In aqueous solution at 25 °C.
and 0.17 ( 0.13, and poor correlation coefficients, r ) 0.260
and 0.398.
Substituent Effects on Quinone Methide Reactivity. Data
that allow the overall rate constant for acid-catalyzed hydration
+
of quinone methides, kH , to be broken down into its constituent
parts, that is, into the acidity constant of the carbocationic
intermediate, KSH, and the rate constant for capture of this
intermediate by water, k′w, are now available for three quinone
methides. The values that result, listed in Table 2, show that
introduction of an R-phenyl substituent and then replacement
of that by a p-anisyl group produce a steady increase in pKSH
and thus an increase in substrate basicity. This is as expected,
inasmuch as these substituents stabilize the positive charge of
the carbocationic intermediate, and p-anisyl is better at positive
charge stabilization than is phenyl. This increasing carbocation
stability also leads to a steadily diminishing rate of capture of
the carbocation by water, again as expected. The overall rate
constant, however, changes in the opposite, perhaps unexpected,
direction. This is because the overall rate constant is equal to
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support of this work. This paper is dedicated to Professor Herbert
C. Brown on the occasion of his 90th birthday.
+
the ratio of k′w to KSH, kH ) k′w/KSH, and the substituent effect
on KSH is stronger than that on k′w, causing the two rate constants
to change in opposite directions. The stronger substituent effect
on KSH than on k′w is, of course, a consequence of the fact that
the equilibrium process represented by KSH involves a full unit
change in substrate positive charge, whereas the kinetic process
represented by k′w involves only a fractional, and therefore
somewhat smaller, change in this charge.
Supporting Information Available: Tables S1-S9 of rate
data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0120375
9
722 J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002