Flash photolytic generation and study of p-Quinone methide in aqueous solution. An estimate of rate and equilibrium constants for heterolysis of the carbon-bromine bond in p-hydroxybenzyl bromide

Article abstract of DOI:10.1021/ja020020w

Flash photolysis of p-hydroxybenzyl acetate in aqueous perchloric acid solution and formic acid, acetic acid, biphosphate ion, and tris(hydroxymethyl)methylammonium ion buffers produced p-quinone methide as a short-lived species that underwent hydration t

Full text of DOI:10.1021/ja020020w

Published on Web 05/09/2002
Flash Photolytic Generation and Study of p-Quinone Methide
in Aqueous Solution. An Estimate of Rate and Equilibrium
Constants for Heterolysis of the Carbon-Bromine Bond in
p-Hydroxybenzyl Bromide
Y. Chiang, A. J. Kresge,* and Y. Zhu
Contribution from the Department of Chemistry, UniVersity of Toronto
Toronto, Ontario M5S 3H6, Canada
Received January 3, 2002
Abstract: Flash photolysis of p-hydroxybenzyl acetate in aqueous perchloric acid solution and formic acid,
acetic acid, biphosphate ion, and tris(hydroxymethyl)methylammonium ion buffers produced p-quinone
methide as a short-lived species that underwent hydration to p-hydroxybenzyl alcohol in hydronium ion
catalyzed (kH ) 5.28 × 104 M-1 s-1) and uncatalyzed (kuc ) 3.33 s-1) processes. The inverse nature of
+
+
+
the solvent isotope effect on the hydronium ion-catalyzed reaction, kH /kD ) 0.41, indicates that this process
occurs by rapid and reversible protonation of the quinone methide on its carbonyl carbon atom, followed
by rate-determining capture of the p-hydroxybenzyl carbocation so produced by water, while the magnitude
of the rate constant on the uncatalyzed process indicates that this reaction occurs by simple nucleophilic
addition of water to the methylene group of the quinone methide. p-Quinone methide also underwent
hydronium ion-catalyzed and uncatalyzed nucleophilic addition reactions with chloride ion, bromide ion,
thiocyanate ion, and thiourea. The solvent isotope effects on the hydronium ion-catalyzed processes again
indicate that these reactions occurred by preequilibrium mechanisms involving a p-hydroxybenzyl carbocation
intermediate, and assignment of a diffusion-controlled value to the rate constant for reaction of this cation
with thiocyanate ion led to KSH ) 110 M as the acidity constant of oxygen-protonated p-quinone methide.
In a certain perchloric acid concentration range, the bromide ion reaction became biphasic, and least-
8
squares analysis of the kinetic data using a double-exponential function provided kBr ) 3.8 × 10 M-1 s-1
as the rate constant for nucleophilic capture of the p-hydroxybenzyl carbocation by bromide ion, kionz ) 8.5
× 102 s-1 for ionization of the carbon-bromine bond of p-hydroxybenzyl bromide, and K ) 4.5 × 105 M-1
as the equilibrium constant for the carbocation-bromide ion combination reaction, all in aqueous solution
at 25 °C. Comparisons are made of the reactivity of p-quinone methide with p-quinone R,R-bis-
(trifluoromethyl)methide as well as p-quinone methide with o-quinone methide.
-
Quinone methides are short-lived reactive species with
interesting chemical properties and pronounced biological
activity.1 We have undertaken a program of research designed
to study the chemistry of these substances in aqueous solution
and have already reported on our work with the parent ortho
isomer 12 and a few of its substituted analogues.3 In this paper,
chemistry of the p-hydroxybenzyl cation (3) through which the
acid-catalyzed reactions of p-quinone methide occur. In par-
ticular, we have been able to provide an estimate of the rate
and equilibrium constants for the reaction of this cation with
bromide ion to give p-hydroxybenzyl bromide (4), eq 1.
We generated p-quinone methide by photolysis of p-hydroxy-
benzyl acetate (5), eq 2, and, because the reactions of this
we add to that an examination of the parent para isomer 2. Our
investigation has also provided some information on the
(1) See, for example: Wan, P.; Barker, B.; Diao, L.; Fischer, M.; Shi, Y.;
Yang, C. Can. J. Chem. 1996, 24, 465-475.
(2) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123, 8089-
8094.
(3) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am Chem. Soc. 2002, 124, 717-722.
Chiang, Y.; Kresge, A. J.; Zhu, Y. Photochem. Photobiol. Sci. 2002, 1,
67-70.
9
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J. AM. CHEM. SOC. 2002, 124, 6349-6356
6349

A R T I C L E S
Chiang et al.
quinone methide in the wholly aqueous solvent that we used
were rapid, we employed flash photolytic methods to follow
their course.
We found further that flash photolysis of the acetic acid ester
of p-hydroxybenzyl alcohol, 5, did produce a good transient
signal, with the strong absorbance at λ ) 300 nm expected of
p-quinone methide. In addition, HPLC product analysis of spent
reaction mixtures from flash photolysis of p-hydroxybenzyl
acetate in 0.001 M perchloric acid as well as in acetic acid and
biphosphate ion buffers showed that this substance was con-
verted to p-hydroxybenzyl alcohol (6), as expected for the
generation and subsequent hydration of p-quinone methide, eq
5. Further evidence that this transient species is p-quinone
methide (2) comes from its chemical behavior detailed below.
Experimental Section
Materials. p-Hydroxybenzyl acetate (5) was prepared by treating
p-hydroxybenzyl alcohol (6) with acetic anhydride in the presence of
boron trifluoride etherate;4 its 1H NMR spectrum agreed with published
reports.5 All other materials were best available commercial grades.
Kinetics. Rate measurements were made using a microsecond flash
photolysis system that has already been described.6 Initial substrate
(p-hydroxybenzyl acetate) concentrations were of the order of 1 × 10-4
M, and the temperature of all reacting solutions was controlled at 25.0
( 0.05 °C. Reactions were monitored by following the decay of
p-quinone methide absorbance at λ ) 300-310 nm. The data so
obtained, for the most part, conformed to the first-order rate law well,
and observed first-order rate constants were obtained by least-squares
fitting of an exponential function. In some of the slower runs, however,
exponential decay was followed by a small downward drift that could
have been due either to instability of the monitoring light source power
supply or to incursion of double-exponential behavior; in these cases,
the fitting was done using a single-exponential plus linear function. In
some of the runs carried out in sodium bromide solutions, this
downward drift developed into a second exponential, and the data were
then analyzed using a double-exponential expression.
Hydration Reaction Rate Profile. Rates of reaction of
p-quinone methide were measured in dilute aqueous (H2O and
D2O) perchloric acid solutions and in formic acid, acetic acid,
biphosphate ion, and tris(hydroxymethyl)methylammonium ion
buffers. The ionic strength of these solutions was maintained
at 0.10 M by the addition of sodium perchlorate as needed.
The data so obtained are summarized in Tables S1 and S2
(Supporting Information).8
The rate measurements in buffers were made in series of
solutions of fixed buffer ratio, and therefore fixed hydronium
ion concentration, but varying buffer concentration. Observed
first-order rate constants proved to be linear functions of buffer
concentration, and the data were therefore analyzed by least-
squares fitting of the buffer dilution expression shown in eq 6.
Product Analysis. The products formed by flash photolysis of
p-hydroxybenzyl acetate were examined by HPLC using a Varian Vista
5500 instrument with a NovoPak C18 reversed-phase column and
methanol-water (50/50, v/v) as the eluent. Reaction solutions, whose
temperature was controlled at 25.0 ( 0.05 °C, were subjected to one
flash from the microsecond system, and products were identified by
comparing UV spectra and retention times with those of authentic
samples. Initial p-hydroxybenzyl acetate concentrations were similar
to those used for the kinetic measurements.
Results
Reaction Identification. We2,3 and others1,7 have found that
the corresponding o-hydroxybenzyl alcohols are good substrates
for the photochemical generation of o-quinone methides. In the
present work, however, we found that flash photolysis of
p-hydroxybenzyl alcohol (6) failed to produce a useful transient
signal. This perhaps surprising difference between ortho and
para isomers is consistent with the much lower quantum yield
reported for the generation of p-quinone R-phenylmethide (7)
from R-phenyl-p-hydroxybenzyl alcohol (8), eq 3, than that for
generation of o-quinone R-phenylmethide (9) from R-phenyl-
o-hydroxybenzyl alcohol (10), eq 4;1,7 quantum yields for the
generation of p-quinone methides are also usually lower than
those for the generation of o-quinone methides.1,7
kobs ) kint + kcat[buffer]
(6)
The zero-buffer concentration intercepts, kint, obtained in this
way, together with the perchloric acid data, were then used to
construct the rate profiles shown in Figure 1. Hydronium ion
concentrations of the buffer solutions needed for this purpose
were obtained by calculation using thermodynamic acidity
constants of the buffer acids from the literature and activity
coefficients recommended by Bates.9
These rate profiles show acid-catalyzed and uncatalyzed
portions; the data were therefore analyzed using the rate law of
+
eq 7. Least-squares fitting gave the results kH ) (5.28 ( 0.03)
× 104 M-1 s-1, kH /kD ) 0.409 ( 0.005 and (kuc)H O ) (3.33
+
+
2
( 0.08) s-1, (kuc)H O /(kuc)D O ) 1.46 ( 0.07.
2
2
kobs ) kuc + k [L+]
(7)
+
L
(4) Cottet, F.; Cottier, L.; Descote, G. Can. J. Chem. 1990, 68, 1251-1257.
(5) Nago, Y.; Fujita, E.; Kohno, T.; Yogi, M. Chem. Pharm. Bull. 1981, 29,
3202-3207. Allevi, P.; Ciuffreda, P.; Longo, A.; Anastasia, M. Tetrahedron
Asymmetry 1998, 9, 2915-2924.
(6) Chiang, Y.; Hojatti, M.; Keeffe, J. R.; Kresge, A. J.; Schepp, N. P.; Wirz,
J. J. Am. Chem. Soc. 1987, 109, 4000-4009.
(7) Diao, L.; Yang, C.; Wan, P. J. Am. Chem. Soc. 1995, 117, 5369-5370.
(8) Supporting Information; see paragraph at the end of this paper regarding
availability.
9
6350 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002

Flash Photolytic Generation of p-Quinone Methide
A R T I C L E S
Figure 3. Relationship between slopes of plots such as that shown in Figure
2 and perchloric acid concentration for the reaction of p-quinone methide
and thiocyanate ion in H2O (O) and D2O (4) solutions at 25 °C.
Figure 1. Rate profiles for the hydration of p-quinone methide in H2O
(O) and D2O (4) solutions at 25 °C.
Table 1. Rate Constants for the Uncatalyzed kN,uc and
+
Acid-Catalyzed (kN,L ). Reactions of p-Quinone Methide with
Nucleophiles in Aqueous Solution at 25 °Ca
nucleophile/solvent
kN,uc/M-1 s-1
kN,L /M-2 s-1
+
Cl-/H2O
Cl-/D2O
(1.10 ( 0.16) × 103 (5.43 ( 0.06) × 105
(1.26 ( 0.31) × 103 (1.52 ( 0.02) × 106
H2O/D2O: 0.88 ( 0.25
0.356 ( 0.06
Br-/H2O
Br-/D2O
(2.02 ( 0.86) × 104 (3.44 ( 0.23) × 106
(0.84 ( 5.26) × 103 (9.62 ( 0.38) × 106
H2O/D2O:
-
0.357 ( 0.028
SCN-/H2O
SCN-/D2O
(2.72 ( 0.71) × 105 (4.56 ( 0.52) × 107
(2.22 ( 0.54) × 105 (8.29 ( 0.38) × 107
H2O/D2O: 1.23 ( 0.44
0.550 ( 0.068
thiourea/H2O
thiourea/D2O
(4.82 ( 0.45) × 105 (3.95 ( 0.33) × 107
(5.10 ( 0.44) × 105 (5.32 ( 0.32) × 107
H2O/D2O: 0.94 ( 0.12
0.743 ( 0.076
H2O
D2O
3.33 ( 0.08b
(5.28 ( 0.03) × 104c
(1.29 ( 0.02) × 105c
0.41 ( 0.017
2.29 ( 0.10b
Figure 2. Relationship between observed rate constants and nucleophile
concentration for the reaction of p-quinone methide with thiocyanate ion
in aqueous solutions (H2O) containing 0.0050 M perchloric acid at 25 °C.
H2O/D2O: 1.46 ( 0.07
a Ionic strength, 0.10 M (NaClO4). b s-1 c M-1 s-1
. .
Reaction with Nucleophiles. The decay of p-quinone methide
in aqueous solution was strongly accelerated by chloride,
bromide, and thiocyanate ions and also by thiourea, in keeping
with the nucleophilic nature of these reagents and the propensity
of quinone methides to react with nucleophiles. These accelera-
tions were also catalyzed by perchloric acid. Rate measurements
were consequently made in series of solutions of fixed perchloric
acid concentration but varying nucleophile concentration, using
both H2O and D2O as the solvent. The ionic strength of these
solutions was kept at 0.10 M by adding sodium perchlorate as
required. The data so obtained are summarized in Tables S3-
S6 (Supporting Information).8
As Figure 2 illustrates, observed first-order rate constants
determined at fixed acid concentrations in this way increased
linearly with increasing nucleophile concentration. Figure 3
shows further that the slopes of such plots, ∆kobs/∆[Nuc],
themselves increased linearly with increasing acidity, according
to the relationship of eq 8. Linear least-squares analysis then
These rate measurements in bromide ion solutions were
performed at perchloric acid concentrations in the range [HClO4]
) 0.02-0.05 M where the decay of p-quinone methide
absorbance conformed to a single-exponential rate law, followed
sometimes by a slower downward drift for solutions at the lower
end of this acidity range. Below [HClO4] ) 0.02 M, however,
this drift developed into a second exponential function.
Additional rate measurements were therefore made over the
concentration range [HClO4] ) 0.005-0.015 M, and the data
were analyzed by least-squares fitting of a double-exponential
function. These results are summarized in Table S7 (Supporting
Information).8
Discussion
Hydration. The rate profiles of Figure 1 represent reaction
of p-quinone methide with solvent-related species through a
process that product analysis shows produces p-hydroxybenzyl
alcohol. The inverse (kH/kD < 1) nature of the solvent isotope
∆kobs/∆[Nuc] ) kN,uc + kN,L+[L+]
(8)
+
+
effect on the acid-catalyzed portion of this process, kH /kD
)
0.41, implies that this reaction occurs by a preequilibrium
substrate protonation mechanism,10 which in this case can be
formulated as rapid and reversible protonation of the quinone
+
,
produced the uncatalyzed, kN,uc, and acid-catalyzed, kN,L
nucleophile rate constants listed in Table 1.
(9) Bates, R. G. Determination of pH Theory and Practice; Wiley: New York,
(10) Keeffe, J. R.; Kresge, A. J. In InVestigation of Rates and Mechanisms of
Reactions; Bernasconi, C. F., Ed.; Wiley: New York, 1986; pp 747-790.
1973; p 49.
9
J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6351

A R T I C L E S
Chiang et al.
methide on its carbonyl oxygen atom, through proton transfer
from the hydronium ion, followed by rate-determining capture
of the ensuing carbocation by a molecule of water, eq 9. The
inverse nature of this isotope effect stems from the fact that
positively charged O-H bonds, such as those in the hydronium
ion, are looser than uncharged O-H bonds, such as those in a
water molecule;11 conversion of H3O+ into H2O in the preequi-
librium step of eq 9 then is accompanied by a tightening of
O-H bonds, and that leads to an inverse isotope effect.
Such a preequilibrium process is confirmed as a general
reaction mechanism for acid-catalyzed quinone methide hydra-
tion by the saturation of acid catalysis observed in the case of
more basic substrates:3 increasing the hydronium ion concentra-
tion in these cases shifts the position of the preequilibrium
reaction from unprotonated to protonated substrate. The proto-
nated substrates then become the reaction’s initial state, and
acid catalysis ceases to operate.
Figure 4. Relationship between the nucleophilic reactivity parameter ηCH I
and second-order rate constants for the uncatalyzed reaction of p-quinon3e
methide with nucleophiles in aqueous solution at 25 °C.
that applies to the reaction scheme of eq 10 is kuc ) kK, with
K, the equilibrium constant for the first step, equal to the acidity
constant of water, Kw, divided by the acidity constant of the
protonated substrate, KSH: kuc ) kKw/KSH. A value of KSH has
not been determined directly, but the estimate KSH ) 102 M
can be made (vide infra). Combination of that with Kw ) 1 ×
10-14 M2 and kuc ) 3.3 s-1 then leads to k ) 3 × 1016 M-1
s-1, which exceeds the encounter-controlled limit by a consider-
able margin.
The uncatalyzed hydration reaction represented by the
horizontal portions of the rate profiles of Figure 1 might occur
by an analogous preequilibrium process, shown in eq 10, in
This leaves the nucleophilic route of eq 11 as the reaction
mechanism for uncatalyzed hydration of p-quinone methide.
Support for this assignment comes from the isotope effect on
this reaction, (kuc)H O/(kuc)D O ) 1.46, which is consistent with
2
2
the development of positive charge on, and the consequent
weakening of, the O-H bonds of the attacking water molecule.
This reaction mechanism is also consistent with the propensity
of quinone methides to react with nucleophiles. A similar
mechanism has been proposed for the uncatalyzed hydration
of o-quinone methide.2
Reaction with Nucleophiles. The results listed in Table 1
show that the reactions of p-quinone methide with thiourea and
chloride, bromide, and thiocyanate ions are acid catalyzed and
that in most cases an uncatalyzed reaction can be detected as
well. These reagents are all good nucleophiles, and it seems
reasonable to conclude that the uncatalyzed reactions are
processes analogous to the mechanism given for the uncata-
lyzed hydration reaction in eq 11, with these nucleophiles taking
the place of the water molecule. This assignment is supported
by Figure 4, which shows that the rate constants for these
uncatalyzed reactions plus that for uncatalyzed hydration
which rapid and reversible substrate protonation occurs by
proton transfer from a water molecule to the quinone methide
carbonyl oxygen atom, and this is then followed by rate-
determining combination of the carbocation and hydroxide ion
thus formed. Uncatalyzed hydration might also take place by
simple rate-determining nucleophilic addition of a water mol-
ecule to the substrate’s methide carbon atom, giving a zwitter-
ionic intermediate, followed by rapid proton relocation, as shown
in eq 11.
correlate well with Pearson’s nucleophilic reactivity constants
12
ηCH I
.
This assignment is also consistent with the solvent
3
isotope effects on these reactions listed in Table 1, which, though
not very precisely determined, nevertheless cluster about unity.
Solvent water plays only a passive role in these reactions: there
is some rearrangement of solvent shells but no serious changes
in solvent O-H bond strength. Since isotope effects on solvent
shells are known to be weak,11,15 this mechanism would be
expected to give solvent isotope effects near unity, as observed.
The first of these reaction mechanisms can be ruled out
because the data would require an impossibly large value of
the rate constant for the rate-determining step, k. The rate law
(12) Pearson, R. G.; Sobel, H.; Songstad, J. J. Am. Chem. Soc. 1968, 90, 319-
326. The value ηCH I ) 0.00 for water was derived from ηCH Br ) 0.00 13
(11) Kresge, A. J.; More O’Ferrall, R. A.; Powell, M. F. In Isotopes in Organic
3
3
14
Chemistry; Buncel, E., Lee, C. C., Eds.; Elsevier: New York, 1987; Chapter
for this substance and the relationship ηCH I ) 1.4 ηCH Br
.
3
4.
(13) Swain, C. G.; Scott, C. B. J. Am. Chem. S3oc. 1953, 75, 141-147.
9
6352 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002

Flash Photolytic Generation of p-Quinone Methide
A R T I C L E S
Table 2. Estimated Rate Constants for the Reaction of
Nucleophiles with the p-Hydroxybenzyl Cation in Aqueous Solution
at 25 °Ca
encounter-controlled process as well as the reaction of this cation
with thiocyanate ion, and the slightly greater value of kN for
thiocyanate may be attributed to an electrostatic effect accelerat-
ing the interaction of two ions of opposite charge. The estimate
kN ) 5.8 × 106 s-1 for the water reaction is less than 2 × 108
s-1 estimated for the p-methoxybenzyl cation 11 reacting with
water in a 50:50 trifluoroethanol-water solvent,16 but that is
consistent with the known greater cation-stabilizing ability of
hydroxyl over methoxyl and the consequent lower reactivity of
the hydroxyl-substituted cation.
nucleophile
kN/107 M-1 s-1
H2O
0.58b
6.0
Cl-
Br-
SCN
thiourea
37
500c
433
a Ionic strength, 0.10 M. b First-order rate constant in units of s-1
c Assigned value.
.
Double-Exponential Behavior. Under certain conditions of
perchloric acid concentration, detailed in Table S7 (Supporting
Information),8 the decay of p-quinone methide absorbance in
sodium bromide solutions became biphasic and analysis of the
kinetic data required use of a double-exponential expression.
Such behavior has been noted before in the reaction of
triphenylmethyl cation with bromide ion in a partly aqueous
solvent, and it was attributed to reversible combination of the
cation with bromide ion accompanied by nonreversible reaction
of the cation with water, eq 13.17 A similar interpretation
The isotope effects on the acid-catalyzed nucleophilic reac-
tions, on the other hand, are all quite strongly inverse (see Table
1). This implies that acid catalysis of these nucleophile reactions
occurs by a preequilibrium mechanism as shown in eq 12,
similar to that assigned above to acid-catalyzed hydration.
Observed rate constants for this process are then equal to rate
constants for the rate-determining nucleophile capture step, kN,
divided by the acidity constant of the quinone methide conjugate
acid, KSH:kobs ) kN/KSH
It is likely that the reaction of thiocyanate ion with the
p-hydroxybenzyl cation 3 in the rate-determining step of the
.
involving the reaction of bromide ion with the p-hydroxybenzyl
cation may be made here.
The present experiments were done in wholly aqueous
solution under conditions where the concentration of the cation
was very much less than that of bromide ion. The system
therefore reduces to a combination of first-order reactions, for
which there is an analytical solution.18 The expression for the
concentration of R+ as function of time is given by eq 14, with
γ1 and γ2
route of eq 12 is an encounter-controlled process. This cation
should be of comparable stability to the p-methoxybenzyl cation
11, which reacts with azide ion at the encounter-controlled
limit.16 Since thiocyanate ion is a stronger nucleophile than azide
ion,12,13 the reaction of p-hydroxybenzyl cation with thiocyanate
ion should be an encounter-controlled reaction as well.
A similar argument was made before for the reaction of
thiocyanate ion with o-hydroxybenzyl cation 12, generated by
protonation of o-quinone methide, and an encounter-controlled
rate constant of 5 × 109 M-1 s-1 was assigned to that reaction.2
Assignment of the same value to the rate constant for reaction
of thiocyanate ion with p-hydroxybenzyl cation, coupled with
the experimental result kN/KSH ) 4.6 × 107, leads to the estimate
KSH ) 110 M. This result can then be used in conjunction with
the experimental rate constants kN/KSH for other nucleophiles
to estimate additional values of kN. The results so obtained are
listed in Table 2.
k2 - γ1
γ2 -γ1
k2 - γ2
γ2 - γ1
[R+] ) [R+]o
e-γ t
-
e-γ t
(14)
1
2
{
}
k + k + k - (k + k + k )2 - 4k k
x
1
2
3
1
2
3
2
3
3
γ1 )
γ2 )
(15)
(16)
2
k + k + k + (k + k + k )2 - 4k k
x
1
2
3
1
2
3
2
2
consisting of the individual step rate constants, k1-k3, defined
by eq 13, as shown in eqs 15 and 16. These individual step rate
constants can be evaluated from the parameters obtained by
least-squares fitting of the experimental data using the empirical
relationship of eq 17; the expressions relating the rate constants
Thiourea is a stronger nucleophile than thiocyanate ion:
η
) 7.27 and 6.70, respectively.12 It seems likely therefore
CH2I
A ) A0 + A1e-Rt + A2e-ât
(17)
that the reaction of p-hydroxybenzyl cation with thiourea is an
(14) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827-1836.
(15) Albery, W. J. In Proton-Transfer Reactions; Caldin, E. F., Gold, V., Eds.;
Chapman and Hall: London, 1975; pp 282-285.
(17) McClelland, R. A.; Banait, N.; Steenken, S. J. Am. Chem. Soc. 1986, 108,
7023-7027.
(18) Capellos, C.; Bielski, B. Kinetic Systems; Wiley-Interscience: New York,
1972; pp 73-75.
(16) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1990, 112, 9507-9512.
9
J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6353

A R T I C L E S
Chiang et al.
the third-order rate constant for nucleophilic capture of the
p-hydroxybenzyl cation by bromide ion; it is gratifying that its
value, kBr /KSH ) (3.49 ( 0.69) × 106 M-2 s-1, agrees well
-
with that, kBr /KSH ) (3.44 ( 0.23) × 106 M-2 s-1, determined
-
under single-exponential decay conditions (vide supra). This
good agreement lends credence to this treatment of the double-
exponential data.
Further support for this method of analysis comes from the
behavior of k2 and k3. The rate constant k2 proved to be
independent of both bromide ion and perchloric acid concentra-
tions, as expected for the simple ionization of p-hydroxybenzyl
bromide. Its best value, k2 ) (8.45 ( 0.27) × 102 s-1, was
therefore determined as the simple average of all of the (85)
individual values obtained. The rate constant k3, on the other
hand, though independent of bromide ion concentration, did
increase linearly with increasing perchloric acid concentration.
This is consistent with k3 being the rate constant for hydration
of the p-hydroxybenzyl cation, a process that does require the
acid-induced generation of this cation but does not involve
bromide ion. Linear least-squares analysis of the relationship
Figure 5. Relationship between the rate constant k1 defined by eq 13 and
bromide ion concentration at a fixed perchloric acid concentration of 0.010
M in aqueous solution at 25 °C.
between k3 and acid concentration produced the acid-catalyzed
hydration rate constant, kH ) (2.92 ( 1.29) × 104 M-1 s-1
,
+
4
-1
+
which is not inconsistent with kH ) (5.28 ( 0.03) × 10 M
s-1 obtained from the hydration rate profile.
These double-exponential rate measurements were made by
monitoring the decay of p-quinone methide, and conversion of
the results into rate constants referred to the p-hydroxybenzyl
cation as the initial state requires application of the equilibrium
constant KSH relating the cation to the quinone methide. Use of
the value KSH ) 110 M estimated above from the thiocyanate
ion reaction then gives kBr- ) (3.49 × 106)(1.10 × 102) ) 3.8
× 108 M-1 s-1 as the rate constant for the reaction of the
p-hydroxybenyl cation with bromide ion, eq 21. This result may
Figure 6. Relationship between slopes of plots such as that shown in Figure
5 and perchloric acid concentration.
to these empirical parameters are given by eqs 18-20.
A1â + A2R
-
be combined with k2 () kionz) to give K ) kBr /kionz ) 4.5 ×
k2 )
105 M-1 as the equilibrium constant for this reaction. This result
shows that un-ionized p-hydroxybenzyl bromide is much more
stable than p-hydroxybenzyl cation and bromide ion. The un-
ionized bromide, however, does not persist in aqueous solution
because ionization followed by capture of the cation so formed
by water provides a facile route to the still more stable
p-hydroxybenzyl alcohol hydration product.
A1 + A2
k3 ) ab/k2
(19)
(20)
k1 ) R + â - k2 - k3
Double-exponential rate measurements were made in series
of solutions of fixed perchloric acid concentration ([HClO4] )
0.005, 0.01, and 0.015 M) but varying bromide ion concentration
([Br-] ) 0.01-0.04 M). The values of k1, k2, and k3 obtained
from these measurements through the use of the relationships
of eqs 17-20 are listed in Table S7 (Supporting Information).8
As is illustrated in Figure 5, the rate constant k1 determined
at a given constant acidity increased regularly in a linear fashion
with increasing bromide ion concentration, as expected for the
p-hydroxybenzyl cation plus bromide ion combination reaction.
Figure 6 illustrates further that the slopes of plots such as that
shown in Figure 5 themselves increased with increasing acid
concentration, again as expected inasmuch as the p-hydroxy-
benzyl cation is produced from p-quinone methide by an acid-
catalyzed reaction. The slope of the plot shown in Figure 6 is
Comparison of p-Quinone Methide with p-Quinone R,R-
Bis(trifluoromethyl)methide. The results obtained here for the
acid-catalyzed addition of bromide ion to p-quinone methide
provide a striking contrast with those reported for the corre-
sponding reaction of p-quinone R,R-bis(trifluoromethyl)methide
(13), eq 22.19 The mechanisms of these two reactions are not
the same: the hydronium ion isotope effect on the reaction of
9
6354 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002

Flash Photolytic Generation of p-Quinone Methide
A R T I C L E S
Table 3. Comparison of the Acid-Catalyzed Reaction of Bromide
Ion with p-Quinone Methide, 2, and with p-Quinone R,
R-Bis(trifluoromethyl)methide, 13
Table 4. Comparison of o- and p-Quinon Methidesa
quantity
kuc/s-1
o-isomer
p-isomer
o/p
2.6 × 102
5.2 × 101
4.4 × 107
1.1 × 109
8.4 × 105
3.3
78
2a
13b
K
SH/M
1.1 × 102
5.8 × 106
3.7 × 108
5.3 × 104
0.47
7.6
2.9
16
K/M-2
4.1 × 103
6.4 × 104
kw/s-1
∆G°/kcal mol-1
k/M-2 s-1
-4.9
-6.6
kBr /M-1 s-1
-
3.4 × 106
3.7
16.7
19.8
kH /M-1 s-1
+
∆G‡/kcal mol-1
∆G‡o/kcal mol-1
8.5
a Aqueous solution; 25 °C; ionic strength, 0.10 M.
10.9
a Aqueous solution, 25 °C, ionic strength ) 0.10 M (NaClO4). b Data
from ref 19; 50:50 (V/V) trifluoroethanol/water, 25 °C, ionic strength )
0.50 (NaClO4).
will be lost, and that loss will run ahead of covalent bond
formation,23 creating an imbalance that will lower kinetic
reactivity and augment the intrinsic barrier.24 Because trifluoro-
methyl groups are strongly electron-withdrawing, they will
destabilize the canonical resonance form of the carbocation with
positive charge on the benzyl carbon atom 14, decreasing its
contribution and increasing the contribution of the delocalized
forms represented by 15. The fluorinated cation will therefore
have more resonance stabilization to be lost, will suffer from
more imbalance in its transition state, and will be the more
intrinsically slow reactant.
the fluorinated substrate is unity rather than inverse,19 which
indicates that proton transfer and bromide ion capture here are
concerted and not stepwise as in the reaction of the unfluorinated
substrate, eq 12. The hypothetical stepwise reaction of the
fluorinated substrate, because it does not occur, must therefore
be slower than the observed concerted reaction, and the rate
constant observed can consequently serve as an upper limit for
that of the stepwise reaction.
Comparison of o- and p-Quinone Methide. Some of the
measurements made here on p-quinone methide have also been
carried out on o-quinone methide,2 and it is of interest to
compare the results obtained for the two systems. The relevant
data are summarized in Table 4.
It may be seen that the rate of uncatalyzed hydration,
measured by the rate constant kuc, is nearly 80 times greater for
o-quinone methide than for p-quinone methide. This undoubt-
edly is a reflection of the greater stability of p-quinoid over
o-quinoid structures, as evidenced for example by the well-
known greater stability of p-benzoquinone over o-benzoqui-
none.25
The protonation of o-quinone methide on its carbonyl oxygen
atom also takes place more readily than the corresponding
reaction for the para isomer, as shown by the weaker acidity of
o-quinone methide over p-quinone methide. The ratio of the
basic strengths, however, (1/0.47 ) 2.1) is considerably less
than the ratio of the uncatalyzed hydration rate constants (78).
This suggests that a considerable portion of the unprotonated
quinone methide stability difference is maintained in the
conjugate acids, i.e., that the protonated substrates have retained
considerable quinone methide character. This is consistent with
the known strong cation-stabilizing ability of the hydroxyl group
and the consequent expected importance of the quinoid canonical
form in the resonance hybrid structure of the quinone methide
conjugate acid, as illustrated for the para isomer by the scheme
of eq 24.
The data assembled in Table 3 show that the driving forces
of the two reactions, as measured by the equilibrium constants,
K, are closely similar: the corresponding free energies of
reaction, ∆G°, differ by only 1.7 kcal mol-1. The rate constants
k, on the other hand, are quite different and give free energies
of activation, ∆G‡, that differ by 8.2 cal mol-1. These quantities
may be converted into intrinsic barriers, ∆G‡o, which measure
intrinsic kinetic reactivity free of any thermodynamic drive or
impediment,20 through the application of Marcus rate theory.21
The results give an intrinsic barrier difference of 8.9 kcal mol-1
,
which, because ∆G‡o for the fluorinated system is a lower limit,
shows that intrinsic barriers for stepwise reactions of the two
substrates must differ by more than this amount.
This strong difference in intrinsic kinetic reactivity can be
understood in terms of an interplay of electrical effects that
operate in the rate-determining bromide ion capture step of these
reactions, eq 23.19,22 The positive charge of the carbocation in
the initial state of this reaction step will be stabilized by
delocalization into the aromatic ring and onto the p-hydroxy
group. As carbon-bromine covalent bond formation occurs in
the transition state of this reaction, this resonance stabilization
The importance of the quinoid form may also be seen in the
greater reactivity toward capture by nucleophiles of the cation
derived from o-quinone methide than that of the cation derived
from p-quinone methide. It is significant also that this reactivity
(19) Richard, J. P. J. Am. Chem. Soc. 1991, 113, 4588-4595.
(20) Kresge, A. J. Acc. Chem. Res. 1975, 8, 354-360.
(21) Marcus, R. A. J. Phys. Chem. 1968, 72, 891-899.
(22) Richard, J. P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001, 34,
981-988.
(23) Kresge, A. J. Can. J. Chem. 1974, 52, 1897-1903.
(24) Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9-16.
(25) Loudon, G. M. Organic Chemistry; Addison-Wesley: Menlo Park, CA,
1984; p 751.
9
J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6355

A R T I C L E S
Chiang et al.
difference is greater in the slower hydration reaction (o/p )
7.6) than in the more rapid bromide ion reaction (o/p ) 2.9),
consistent with the expected greater selectivity of the slower
process.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support of this work.
Supporting Information Available: Tables of rate data. This
material is available free of charge via the Internet at http://
pubs.acs.org. See any current masthead page for ordering
information and Web access instructions.
+
The rate constant kH is of course a complex quantity being
+
made up of kw and KSH: kH ) kw/KSH. Its o/p ratio therefore
contains a contribution of o/p ) 7.6 given by kw and a
contribution of 1/0.47 ) 2.1 given by KSH
.
JA020020W
9
6356 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002