Kinetics and mechanism of hydration of o-thioquinone methide in aqueous solution. Rate-determining protonation of sulfur

Article abstract of DOI:10.1021/jo0402677

(Chemical Equation Presented) o-Thioquinone methide, 2, was generated in aqueous solution by flash photolysis of benzothiete, 1, and rates of hydration of this quinone methide to o-mercaptobenzyl alcohol, 3, were measured in perchloric acid solutions, using H₂O and D₂O as the solvent, and also in acetic acid and tris(hydroxymethyl)methylammonium ion buffers, using H₂O as the solvent. The rate profiles constructed from these data show hydronium-ion-catalyzed and uncatalyzed hydration reaction regions, just like the rate profiles based on literature data for hydration of the oxygen analogue, o-quinone methide, of the presently examined substrate. Solvent isotope effects on hydronium-ion catalysis of hydration for the two substrates, however, are quite different: k_H/k_D = 0.42 for the oxygen quinone methide, whereas k_H/k_D = 1.66 for the sulfur substrate. The inverse nature (k_H/k_D < 1) of the isotope effect in the oxygen system indicates that this reaction occurs by a preequilibrium proton-transfer reaction mechanism, with protonation of the substrate on its oxygen atom being fast and reversible and capture of the benzyl-type carbocationic intermediate so formed being rate-determining. The normal direction (k_H/k_D > 1) of the isotope effect in the sulfur system, on the other hand, suggests that protonation of the substrate on its sulfur atom is in this case rate-determining, with carbocation capture a fast following step. A semiquantitative argument supporting this hypothesis is presented.

Full text of DOI:10.1021/jo0402677

Kinetics and Mechanism of Hydration of o-Thioquinone Methide
in Aqueous Solution. Rate-Determining Protonation of Sulfur
Yvonne Chiang, A. Jerry Kresge,* Oleg Sadovski, and Hao-Qiang Zhan
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
akresge@chem.utoronto.ca
Received September 21, 2004
o-Thioquinone methide, 2, was generated in aqueous solution by flash photolysis of benzothiete, 1,
and rates of hydration of this quinone methide to o-mercaptobenzyl alcohol, 3, were measured in
perchloric acid solutions, using H
tris(hydroxymethyl)methylammonium ion buffers, using H
2
O and D
2
O as the solvent, and also in acetic acid and
O as the solvent. The rate profiles
2
constructed from these data show hydronium-ion-catalyzed and uncatalyzed hydration reaction
regions, just like the rate profiles based on literature data for hydration of the oxygen analogue,
o-quinone methide, of the presently examined substrate. Solvent isotope effects on hydronium-ion
catalysis of hydration for the two substrates, however, are quite different: k
oxygen quinone methide, whereas k /k ) 1.66 for the sulfur substrate. The inverse nature (k
1) of the isotope effect in the oxygen system indicates that this reaction occurs by a preequilibrium
/k
H D
) 0.42 for the
H
D
H
/k
D
<
proton-transfer reaction mechanism, with protonation of the substrate on its oxygen atom being
fast and reversible and capture of the benzyl-type carbocationic intermediate so formed being rate-
H D
determining. The normal direction (k /k > 1) of the isotope effect in the sulfur system, on the
other hand, suggests that protonation of the substrate on its sulfur atom is in this case
rate-determining, with carbocation capture a fast following step. A semiquantitative argument
supporting this hypothesis is presented.
Quinone methides are interesting molecules with wide
substrate: irradiation of benzothiete, 1, leads to opening
of the four-membered ring, which produces o-thioquinone
methide 2, whose hydration to o-mercaptobenzyl alcohol,
3, can be monitored by following the decay of thioquinone
methide UV absorbance.
1
applications in organic synthesis; they also play key roles
2
in wood chemistry and show pronounced biological
3
activity. In living systems where water is the ubiquitous
medium, this biological activity must operate against a
background of wasteful quinone methide hydration reac-
tions. Because little appeared to be known about the
kinetics and reaction mechanisms of these hydrations,
we have undertaken a program of research aimed at
providing some of the lacking information.
Simple quinone methides are quite short-lived in
aqueous solution. They can, however, be generated and
studied in that medium by using flash photolytic meth-
ods, as illustrated in eq 1 for the presently examined
Experimental Section
Materials. Benzothiete was prepared from o-mercaptoben-
4
zyl alcohol via benzooxathiinone. All other materials were best
available commercial grades.
Kinetics. Rates of hydration of o-thioquinone methide were
measured by monitoring the decay of o-thioquinone methide
(
1) Wan, P.; Barker, B.; Dio, L.; Fischer, M.; Shi, Y.; Yang, C. Can
5
J. Chem. 1996, 24, 465-475. Van De Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367-5405.
absorbance at λ ) 460 nm using an eximer laser flash
photolysis system operating at λ ) 248 nm that has already
(
2) Sipila, J.; Brunow, G. Bull. Liaison-Groupe Poyphenols 1992
6
been described. The temperature of reaction mixtures at
1
6, 140-143. Gratz, J. S.; Chen, C. L. In Lignin: Historical, Biological,
which the kinetic measurements were made was controlled
and Materials Perspectives; Glasser, W. G., Northey, R. A., Schultz,
T. P., Eds.; ACS Symposium Series 742; American Chemical Society:
Washington, DC, 200; pp 392-421.
(4) Meier, H.; Mayer, A. Synthesis 1996, 327-329.
(5) Schweig, A.; Diehl, F.; Kesper, K.; Meyer, H. J. Mol. Struct. 1989,
198, 307-325.
(6) Andraos, J.; Chiang, Y.; Huang, G. C.; Kresge, A. J.; Scaiano, J.
J. Am. Chem. Soc. 1993, 115, 10605-10610.
(
3) Peter, M. W. Angew. Chem., Int. Ed. Engl. 1989. 28, 555-570.
Bolon, J. L.; Pisha, E.; Zhang, F.; Qui, S. Chem. Res. Toxicol. 1998,
1, 1113-1127. Veldhuysen, W. F.; Shallop, A. J.; Jones, R. A.; Rokita,
S. E. J. Am. Chem. Soc. 2001, 123, 11126-11132.
1
1
0.1021/jo0402677 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/28/2005
J. Org. Chem. 2005, 70, 1643-1646
1643

Chiang et al.
at 25.0 ( 0.1 °C. The data so obtained conformed to the first-
order rate law well, and observed first-order rate constants
were obtained by least-squares fitting of a single-exponential
function.
Results
It was already known, when we began the present
work, that irradiation of benzothiete (1) causes opening
of its four-membered ring, producing o-thioquinone
methide (2), as shown in eq 1.4 We verified this by
observing that flash photolytic irradiation of benzothiete
gives a transient species whose UV absorbance at λ )
5
4
60 nm is characteristic of o-thioquinone methide. We
also observed that this irradiation, when conducted in
aqueous solution, produces o-mercaptobenzyl alcohol (3),
the expected o-thioquinone methide hydration product (eq
FIGURE 1. Rate profiles for the hydration of o-quinone
1
). This was shown to be so by HPLC analysis using
2 2
methide in H O, O, and D O, 4, solution at 25 °C.
retention times, UV spectra, and spiking with an au-
thentic sample to identify the product.
buffer acids from the literature and activity coefficients
recommended by Bates.10
We measured rates of o-thioquinone methide hydration
in perchloric acid solutions over the concentration range
[
HClO
over the concentration range [DClO
using D O as the solvent. Some rate measurements were
also made in acetic acid and tris(hydroxymethyl)methyl-
ammonium ion buffers using H O as the solvent. These
4
] ) 0.001-4.56 M using H
2
O as the solvent and
kobs ) kint + kbuff[buffer]
(3)
4
] ) 0.001-1.14 M
2
Discussion
2
The rate profiles displayed in Figure 1 are based upon
rate measurements we made in a previous study of the
hydration of o-quinone methide,11 which is the oxygen
analogue of the presently examined o-thioquinone
methide. It may be seen that the hydronium-ion-
catalyzed portion of that reaction occurs more rapidly in
data are summarized in Tables S1 and S2 (Supporting
Information).
The rates of reaction at perchloric acid concentrations
greater than 0.10 M increased more rapidly than in direct
proportion to acid concentration, and the data were
therefore analyzed by the Cox-Yates method using the
X
at the same molar acid concentration. Fitting of the data
7
8
D
2
O solution than in H
2
O solution. This gives the isotope
/k < 1, is
0
acidity function, with X
0
in D
2
O equal to X
0
2
in H O
9
effect k /k
H
D
) 0.42,11 whose inverse nature, k
H
D
classic evidence for a preequilibrium substrate-protona-
tion reaction mechanism,12 which in this case may be
formulated as rapid equilibrium protonation of the
quinone methide on its carbonyl oxygen atom, followed
by rate-determining capture by water of the benzyl-type
carbocation so formed (eq 4). 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
was done using the expression given as eq 2, in which
+
[
L
3
O ] and X
0
are independent variables and kuc and k
L
are rate constants for the uncatalyzed and hydronium-
ion-catalyzed reactions, respectively. Least squares analy-
5
-1
sis produced (kuc
1.21 ( 0.01, and k
) 1.66 ( 0.15.
)
H
) (1.19 ( 0.01) × 10 s , (kuc
H D
) /(kuc)
4
-1 -1
)
H
) (7.04 ( 0.16) × 10 Μ s , k
H
/
k
D
+
mX0
than uncharged O-H bonds such as those in a water
kobs ) kuc + k [L O ]10
(2)
L
3
molecule.13 Conversion of H
O into H
+
O in the equilib-
3
2
rium step of eq 4 then leads to a tightening of the
hydrogenic environment of the species involved, produc-
ing an inverse isotope effect.
The rate measurements in buffers were carried out
using a series of solutions of constant buffer ratio and
constant ionic strength (0.10 M), and therefore constant
hydronium ion concentration, but varying total buffer
concentration. The data within a given series proved to
be linearly proportional to buffer concentration, and the
data were therefore analyzed using the buffer dilution
expression shown as eq 3, in which kbuff is the buffer
catalytic coefficient and kint is the zero-buffer-concentra-
tion intercept. These zero-concentration intercepts, to-
gether with the data obtained from measurements in
perchloric acid solutions, were used to construct rate
This reaction mechanism is supported by saturation
of hydronium-ion catalysis in the case of more basic
substrates such as o-quinone R-phenylmethide, 7, or
profiles for the o-thioquinone methide hydration reaction
(
10) Bates, R. G. Determination of pH Theory and Practice; Wiley:
New York, 1973; p 49.
11) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123,
089-8094
+
(vide infra); values of [H ] needed for this purpose were
(
obtained by calculation, using acidity constants for the
8
(
12) Keeffe, J. R.; Kresge, A. J. In Investigation of Rates and
(
7) Supporting Information; see paragraph at the end of this paper
Mechanisms of Reactions; Bernasconi, C. F., Ed.; Wiley: New York,
1986; Chapter XI.
regarding availability.
(
8) Cox, R. A. Adv. Phys. Org. Chem. 2000, 35, 1-66.
(13) 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; Chapter 4.
(
9) Cox, R. A.; Lam, S.-O.; McClelland, R. A.; Tidwell, T. T. J. Chem.
Soc., Perkin Trans. 2 1979, 272-275.
1644 J. Org. Chem., Vol. 70, No. 5, 2005

Hydration of o-Thioquinone Methide
hydrogens taking on positive charge in its attacking
‡
water molecule, with fractionation factor φOL+ , plus
exchangeable hydrogens in its uncharged X-L bond, with
fractionationfactor φXL‡
.
Two of these three sets of exchangeable hydrogens, those
in the initial state hydronium ion and those in the
transition state attacking water molecule, occur in bonds
to the same kind of atom (oxygen) in the sulfur system
FIGURE 2. Rate profiles for the hydration of o-thioquinone
methide in H O, O, and D O, 4, solution at 25 °C.
2 2
(
eq 5, X ) S) as in the oxygen system (eq 5, X ) O), and
o-quinone R-(p-anisyl)methide, 8.14 With these substrates,
their fractionation factors will therefore cancel in a ratio
of sulfur system to oxygen system isotope effects. This
ratio of isotope effects thus reduces to the simple expres-
sion involving only fractionation factors for the S-H and
O-H bonds in the reaction’s transition state, as shown
in eq 6.
as the hydronium ion concentration increases, the posi-
tion of the preequilibrium shifts over to protonated
substrate; protonated substrate then becomes the reac-
tion’s initial state, further substrate protonation is no
longer necessary, and acid catalysis disappears.
‡
‡
(
k /k ) /(k /k ) ) φ /φSL
(6)
H
D S
H
D O
OL
Hydrogenic fractionation factors are based upon a scale
that assigns a value of unity to factors for uncharged
‡
O-H bonds, and we may therefore take φOL ) 1.00. The
transition state S-H bond in the X ) S version of eq 5 is
Figure 2 shows rate profiles for the hydration of the
sulfur analogue, o-thioquinone methide, constructed us-
ing presently measured rate constants. It may be seen
that the shape of these profiles is similar to those of the
oxygen analogue shown in Figure 1: both have hydro-
nium-ion-catalyzed and uncatalyzed regions. There is,
however, an important difference: whereas the isotope
effect on hydronium-ion catalysis in the oxygen system
was inverse, that for the sulfur system is in the normal
fully formed and uncharged. It is therefore not unlike
‡
the S-H bond in thiophenol, and a value of φSL may
consequently be estimated from the known solvent
isotope effect on the acid ionization of thiophenol (eq 7).
H D
direction: k /k ) 1.66. This suggests that the hydro-
The fractionation factor expression for an equilibrium
process such as this is analogous to that for the rate
nium-ion-catalyzed hydration of o-thioquinone methide
is not occurring by a preequilibrium proton-transfer
reaction mechanism.
process given above, with final state fractionation factors
3
replacing transition state values: (K
a
)
H
/(K )
a D
) φSL/l . Use
This suggestion is reinforced by an estimate of the
isotope effect on such a (hypothetical) preequilibrium
reaction of the thioquinone substrate that can be made
using fractionation factor theory.13 This theory formulates
solvent isotope effects as the product of fractionation
factors for all exchangeable hydrogens in the reaction’s
1
3
16
of l ) 0.69 and (K
a
)
H
/(K
a D
) ) 2.2 then leads to φSL
‡
(
) φSL ) ) 0.72. This result is consistent with φSL ) 0.83
and 0.65 determined for cysteine and 2-mercaptoethane-
sulfonate, respectively.17
We have measured seven solvent isotope effects for
oxygen quinone methides hydrating by the preequilib-
IS
initial state, φ , divided by a similar product of fraction-
rium proton-transfer reaction mechanism.1
1,14,18
Use of
ation factors for all exchangeable hydrogens in the
the average of these values, k
H
/k
OL ) 1.00 and φSL ) 0.72 in eq 6 then leads to (k
0.54 as an estimate of the solvent isotope effect for
D
) 0.39 ( 0.03, plus
‡
IS
‡
reaction’s transition state, φ : k
/k
H D
I j
) Πφ /Πφ . Equa-
‡
‡
φ
H
/k
D S
)
tion 5, in which exchangeable hydrogens are designated
by the symbol “L”, shows that the initial state of a
quinone methide hydration reaction occurring by a pre-
equilibrium proton-transfer mechanism has exchange-
able hydrogens in its hydronium ion, with fractionation
)
o-thioquinone methide hydrating by a (hypothetical)
preequilibrium proton-transfer reaction mechanism. This
estimate is quite different from the measured value k /
H
15
factor l, and that the transition state has exchangeable
(
16) Jencks, W. P.; Salvesen, K. J. Am. Chem. Soc. 1971, 93, 4433-
436.
(17) Jarret, R. M.; Saunders, M. J. Am. Chem. Soc. 1985, 107, 2648-
2654.
4
(
14) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002, 124,
7
17-722.
(15) Symbol “l”, rather than “φ” with an appropriate subscript and/
(18) Chiang, Y., Kresge, A. J.; Zhu, Y. Phys. Chem. Chem. Phys.
2003, 5, 1039-1042. Chang, J. A.; Kresge, A. J.; Zhan. H.-Q.; Zhu, Y.
J. Phys. Org. Chem. 2004, 17, 579-585.
or superscript, is commonly used for the fractionation factor of the
hydronium ion.
J. Org. Chem, Vol. 70, No. 5, 2005 1645

Chiang et al.
k
D
) 1.66, certainly different enough to add good support
rate constant equal to the rotational correlation time of
the solvent water, 1011 s . In the present case, however,
-1 21
to the idea that the hydronium-ion-catalyzed hydratioin
of o-thioquinone methide does not occur by a preequilib-
rium proton-transfer reaction mechanism
Our working hypothesis is that proton transfer to
sulfur is rate-determining in the hydronium-ion catalyzed
hydration of o-thioquinone methide and that this step is
then followed by rapid capture of the benzyl-type car-
bocation thus formed, 9, by a water molecule (eq 8).
k
-1 will be less than this because the reaction converts
an aromatic benzene ring into a cyclohexadiene structure,
giving up some of the benzene resonance energy and
adding to the small diffusional reaction barrier. But k-1
cannot be less than k
w
, which has been estimated at k
) 4 × 10 s , because the oxygen quinone methide
reacts by a preequilibrium mechanism with k-1 > k . A
w
7
-1 11
w
9
-1
reasonable estimate might therefore be k-1 ) 1 × 10 s .
The value of k-1 for the sulfur system will be less than
this because proton transfer to and from sulfur is slower
than that to and from oxygen,19 and a not unreasonable
2
estimate of this retardation might be the factor 10 by
which downhill proton removal from the S-H bond of
The difference between this mechanism and the pre-
equilibrium scheme that operates in the case of oxygen
quinone methides is consistent with the well-known fact
2
-mercaptoethanol is slower than the anticipated diffu-
sion-controlled reaction of the corresponding oxygen
system.1 This puts k-1 for the sulfur quinone methide
9a
that proton transfers to and from sulfur are slower than
9
-2
7
-1
those involving oxygen.19 It is also consistent with the
at k-1 ) (1 × 10 )(10 ) ) 1 × 10 s . It was noted above
that an ortho SH group is less effective than an ortho
OH group at stabilizing the positive charge of the benzyl-
type carbocation intermediate in these quinone methide
hydration reactions. This will make the sulfur system
carbocation more reactive than that in the oxygen system,
poorer ability of an ortho SH group than an ortho OH
group at stabilizing the positive charge of the benzyl-type
carbocation intermediate in these quinone methide hy-
dration reactions, as evidenced, for example, by the
+
resonance substituent constants of these groups: R (SH)
+
20
pushing k
value, k
quinone methide. The net result is to change the oxygen
system inequality k-1 > k into the different inequality
for the sulfur system and thus change the
w
for the sulfur quinone methide above the
)
-0.33 and R (OH) ) -1.25. Each of these differences
7
-1 11
w
) 4 × 10 s , estimated for the oxygen
operates in a way to slow the reverse of the proton-
transfer step and accelerate the subsequent carbocation
capture step, thus changing the preequilibrium reaction
mechanism observed for the oxygen quinone methide into
a rate-determining proton-transfer scheme for the sulfur
quinone methide.
w
k
-1 < k
w
preequilibrium reaction mechanism into a rate-determin-
ing proton transfer reaction scheme.
Although we have been able to make a plausible case
for a reaction mechanism in which proton transfer to
sulfur is rate-determining and subsequent capture of the
benzyl-type cation is a fast following step, we cannot, on
the basis of the evidence we have so far, rule out a
concerted reaction scheme in which proton transfer and
cation capture occur in the sane reaction step. We do
favor the stepwise mechanism, however, and we are
using that as a working hypothesis to guide further
studies, because it is a simple variant of the preequilib-
rium reaction mechanism that is firmly established for
oxygen quinone methide systems.
This conclusion can be supported further by the fol-
lowing approximate quantitative argument. Whether the
generalized reaction of eq 9 occurs by a preequilibrium
mechanism or by a rate-determining proton-transfer
scheme depends on the relative magnitudes of the rate
constants k-1 and k
preequilibrium proton transfer, and if k-1 < k , the
w
w
w
: if k-1 > k , the mechanism is
mechanism is rate-determining proton transfer.
Acknowledgment. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
for financial support of this work.
In the oxygen quinone methide case, k-1 refers to a
downhill oxygen-to-oxygen proton transfer reaction that
would normally be a diffusion-controlled process with a
Supporting Information Available: Tables S1 and S2
of rate data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
19) (a) Kreevoy, M. M.; Sappenfield, D. S.; Schwabacher, W. J. Phys.
Chem. 1965, 69, 2287-2291. (b) Eigen, M.; Kruse, W.; Maass, G. Ber.
Bunsen-Ges. 1970, 74, 380-385.
JO0402677
(
20) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
1
95.
(21) Kaatze, U. J. Chem. Eng. Data 1989, 34, 371-374.
1646 J. Org. Chem., Vol. 70, No. 5, 2005