Dual reactivity of hydroxy- and methoxy- substituted o-Quinone methides in aqueous solutions: Hydration versus tautomerization.

Article abstract of DOI:10.1021/jo101613t

4-Hydroxy-6-methylene-2,4-cyclohexadien-1-one (1) and 4-methoxy-6- methylene-2,4-cyclohexadien-1-one (2) were generated by efficient (Φ = 0.3) photodehydration of 2-(hydroxymethyl)benzene-1,4-diol (3a) and 2-(hydroxymethyl)-4-methoxyphenol (4a), respectively. o-Quinone methides 1 and 2 can be quantitatively trapped as Diels-Alder adducts with ethyl vinyl ether or intercepted by good nucleophiles, such as azide ion (k_N3(1) = 3.15 × 10⁴ M^-1 s^-1 and k_N3(2) = 3.30 × 10⁴ M^-1 s^-1). In aqueous solution, o-quinone methide 2 rapidly adds water to regenerate starting material (τ_H2_O(2) = 7.8 ms at 25 °C). This reaction is catalyzed by specific acid (k_H⁺(2) = 8.37 × 10 ³ s^-1 M^-1) and specific base (k _OH^-(2) = 1.08 × 10⁴ s^-1 M ^-1) but shows no significant general acid/base catalysis. In sharp contrast, o-quinone methide 1 decays (τ_H2_O(1) = 3.3 ms at 25 °C) via two competing pathways: nucleophilic hydration to form starting material 3a and tautomerization to produce methyl-p-benzoquinone. The disappearance of 1 shows not only specific acid (k_H⁺(1) = 3.30 × 10⁴ s^-1 M^-1) and specific base catalysis (k_OH^-(1) = 3.51 × 10⁴ s ^-1 M^-1) but pronounced catalysis by general acids and bases as well. The o-quinone methides 1 and 2 were also generated by the photolysis of 2-(ethoxymethyl)benzene-1,4-diol (3b) and 2-(ethoxymethyl)-4- methoxyphenol (4b), as well as from (2,5-dihydroxy-1-phenyl)methyl- (3c) and (2-hydroxy-5-methoxy-1-phenyl)methyltrimethylammonium iodides (4c). Short-lived (τ_25°C ≈ 20 μs) precursors of o-quinone methides 1 and 2 were detected in the laser flash photolysis of 3a,b and 4a,b. On the basis of their reactivity, benzoxete structures have been assigned to these intermediates.

Full text of DOI:10.1021/jo101613t

pubs.acs.org/joc
Dual Reactivity of Hydroxy- and Methoxy- Substituted o-Quinone
Methides in Aqueous Solutions: Hydration versus Tautomerization.
Selvanathan Arumugam and Vladimir V. Popik*
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
vpopik@chem.uga.edu
Received August 17, 2010
4-Hydroxy-6-methylene-2,4-cyclohexadien-1-one (1) and 4-methoxy-6-methylene-2,4-cyclohexadien-1-one
(2) were generated by efficient (Φ = 0.3) photodehydration of 2-(hydroxymethyl)benzene-1,4-diol (3a) and
2-(hydroxymethyl)-4-methoxyphenol (4a), respectively. o-Quinone methides 1 and 2 can be quantitatively
trapped as Diels-Alder adducts with ethyl vinyl ether or intercepted by good nucleophiles, such as azide ion
(kN3(1) = 3.15 ꢀ 104 M-1 s-1 and kN3(2) = 3.30 ꢀ 104 M-1 s-1). In aqueous solution, o-quinone methide 2
rapidly adds water to regenerate starting material (τH O(2) = 7.8 ms at 25 °C). This reaction is catalyzed by
2
specific acid (kHþ(2) = 8.37 ꢀ 103 s-1 M-1) and specific base (kOH-(2) = 1.08 ꢀ 104 s-1 M-1) butshowsno
significant general acid/base catalysis. In sharp contrast, o-quinone methide 1 decays (τH O(1) = 3.3 ms at
2
25 °C) via two competing pathways: nucleophilic hydration to form starting material 3a and tautomeriza-
tion to produce methyl-p-benzoquinone. The disappearance of 1 shows not only specific acid (kHþ(1) =
3.30 ꢀ 104 s-1 M-1) and specific base catalysis (kOH-(1) = 3.51 ꢀ 104 s-1 M-1) but pronounced catalysis by
general acids and bases as well. The o-quinone methides 1 and 2 were also generated by the photolysis of
2-(ethoxymethyl)benzene-1,4-diol (3b) and 2-(ethoxymethyl)-4-methoxyphenol (4b), as well as from (2,5-
dihydroxy-1-phenyl)methyl- (3c) and (2-hydroxy-5-methoxy-1-phenyl)methyltrimethylammonium iodides
(4c). Short-lived (τ25°C ≈ 20 μs) precursors of o-quinone methides 1 and 2 were detected in the laser flash
photolysis of 3a,b and 4a,b. On the basis of their reactivity, benzoxete structures have been assigned to these
intermediates.
Introduction
biological processes.1-3 The chemical behavior of o-QMs
resembles that of R,β-unsaturated ketones. However, the
zwitterionic resonance form in the former is additionally
stabilized by aromatic conjugation, increasing o-QMs polar-
ity and enhancing their reactivity.1,4 o-QMs react very
rapidly with nucleophiles and undergo efficient Diels-Alder
cycloaddition with electron-rich olefins.1,4 It has been
demonstrated that o-QMs are efficient dDNA alkylating
and cross-linking agents,1,5 and are believed to be res-
ponsible for the cytotoxicity of antitumor antibiotics of mitomy-
cin C and anthracycline families.6
o-Quinone methides (o-QMs) are very reactive species that
have been implicated as intermediates in many chemical and
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Intermediates in Chemistry and Biology, Vol. 1; Wiley: Hoboken, NJ, 2009.
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Xu, M. Pure Appl. Chem. 2001, 73, 529. (b) Wan, P.; Barker, B.; Diao, L.;
Fischer, M.; Shi, Y.; Yang, C. Can. J. Chem. 1996, 74, 465. (c) Petet, M. G.
Angew. Chem., Int. Ed. 1982, 94, 376. (d) Berson, , J. In The chemistry of the
quinonoid compounds; Patai, S, Rappoport, Z., Eds.; Wiley: Chichester, UK,
1988; Vol. 2, Part 1, pp 455-536; (e) Van De Water, R. W.; Pettus, T. R. R.
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V.; Wan, P. Can. J. Chem. 1999, 77, 868. (g) Bulger, P. G.; Bagal, S. K.;
Marquez, R. Nat. Prod. Rep. 2008, 25, 254 and references cited therein.
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Formation, Structure and Reactions; Sarkanen, K. V., Ludving, C., Eds.; Wiley:
New York, 1971. (b) Stowell, J. K.; Widlanski, T. S.; Kutateladze, T. G.; Raines,
R. T. J. Org. Chem. 1995, 60, 6930.
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M. A.; Tormos, R. J. Org. Chem. 2003, 68, 9643. (b) Chiang, Y.; Kresge,
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7338 J. Org. Chem. 2010, 75, 7338–7346
Published on Web 10/06/2010
DOI: 10.1021/jo101613t
r
2010 American Chemical Society

Arumugam and Popik
JOCArticle
o-QMs can be efficiently generated by photodehydration
of o-hydroxybenzyl alcohol derivatives.2a,4a-c The enhanced
acidity of phenols in the excited state facilitates intramole-
cular proton transfer (ESIPT)7 of the phenolic proton to the
oxygen atom in benzylic position.4a-c C-O bond heterolysis
can be concerted with ESIPT or the loss of water might occur
in the ground state after proton transfer is complete.8 In
either case, the formation of o-QMs is usually complete
within a nanosecond pulse.4a-c o-QMs also can be generated
by photochemical elimination of ammonia or amines from
o-hydroxybenzylamines.9
The major reaction of o-QMs in aqueous solutions is rapid
addition of water producing o-hydroxybenzyl alcohol deriva-
tives. Efficacy enhancement of o-QM-based antitumor agents,1
as well as development of o-hydroxybenzyl photolabile protect-
ing groups,10 requires a better understanding of o-QM behavior
in this medium. However, only kinetics of hydration of the
parent o-QM, 6-methylene-2,4-cyclohexadien-1-one, has been
investigated in detail.4b-d Little is known about the influence of
the electronic properties of substituents on the reactivity of
oQMs.4a,5d,11 Our recent studies of o-naphthoquinone methides
have demonstrated that the presence of an additional electron-
rich aromatic ring causes dramatic changes in the mechanism of
formation and reactivity of o-QM.11 These results prompted us
to investigate the effect of electron-donating substituents on the
dynamics of o-quinone methide hydration. In the present report
we discuss the photochemical generation and reactivity of
electron-rich o-quinone methides 1 and 2 (Scheme 1).
FIGURE 1. UV spectra of ca. 10-5 M aqueous solutions of 3a
(solid line) and 4a (dashed line).
SCHEME 1
FIGURE 2. Emission spectra at λex = 266 nm of ca. 10-5
aqueous solutions of 3a (dashed line) and 4a (solid line).
M
from (2,5-dihydroxy-1-phenyl)methyl- (3c) and (2-hydroxy-5-
methoxy-1-phenyl)methyltrimethylammonium iodides (4c).12
The formation and reactions of o-QMs in aqueous solutions
were monitored with a nanosecond kinetic spectrometer
equipped with pulsed Nd:YAG laser.12 The product analysis
of photochemical reactions of 3a-c and 4a-c was conducted by
HPLC, using individual compounds isolated from preparative
scale photolyses as references.
Results and Discussion
o-QMs 1 and 2 are conveniently generated by the photolysis
of 2-(hydroxymethyl)benzene-1,4-diol (3a) and 2-(hydroxy-
methyl)-4-methoxyphenol (4a); 2-(ethoxymethyl) benzene-1,4-
diol (3b) and 2-(ethoxymethyl)-4-methoxyphenol (4b);aswellas
Photophysical Properties and Photochemical Reactivity of
o-QM Precursors. UV spectra of 2-(hydroxymethyl)ben-
zene-1,4-diol (3a) and 2-(hydroxymethyl)-4-methoxyphenol
(4a) are very similar (Figure 1) and red-shifted by 25-30 nm
compared to the spectrum of o-hydroxybenzyl alcohol.13 A
major absorption band of 3a lies at 295 nm (log ε = 3.91) and
of 4a at 300 nm (log ε = 3.97). Both o-QM precursors are
fluorescent showing emission band with λmax at 333 (3a) and
336 nm (4a) (Figure 2). The quantum yield of fluorescence is
(5) (a) Wang, P.; Song, Y.; Zhang, L. X.; He, H. P.; Zhou, X. Curr. Med.
Chem. 2005, 12, 2893. (b) Freccero, M.; Di Valentin, C.; Sarzi-Amade, M.
J. Am. Chem. Soc. 2003, 125, 3544. (c) Weng, X.; Ren, L.; Weng, L.; Huang,
J.; Zhu, S.; Zhou, X.; Weng, L. Angew. Chem., Int. Ed. 2007, 46, 8020. (d)
Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K. N.; Mitchell,
C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc. 2006, 128, 11940. (e)
Wang, P.; Liu, R.; Wu, X.; Ma, H.; Cao, X.; Zhou, P.; Zhang, J.; Weng, X.;
Zhang, X.-L.; Qi, J.; Zhou, X.; Weng, L. J. Am. Chem. Soc. 2003, 125, 1116.
(f) Richter, S. N.; Maggi, S.; Mels, S. C.; Palumbo, M.; Freccero, M. J. Am.
Chem. Soc. 2004, 126, 13973. (g) Colloredo-Mels, S.; Doria, F.; Verga, D.;
Freccero, M. J. Org. Chem. 2006, 71, 3889.
(6) (a) Han, I.; Russell, D. J.; Kohn, H. J. Org. Chem. 1992, 57, 1799. Li,
V.-S.; Kohn, H. J. Am. Chem. Soc. 1991, 113, 275. (b) Tomasz, M.; Das, A.;
Tang, K. S.; Ford, M. G. J.; Minnock, A.; Musser, S.; Waring, M. J. J. Am.
Chem. Soc. 1998, 120, 11581. (c) Egholm, M.; Koch, T. H. J. Am. Chem. Soc.
1989, 111, 8291. (d) Gaudiano, G.; Frigerio, M.; Bravo, P.; Koch, T. H. J. Am.
Chem. Soc. 1990, 112, 6704.
(7) (a) Lahiri, S. C. J. Sci. Ind. Res. 1979, 38, 492. Van der Donckt, E. Prog.
React. Kinet. 1970,5, 273. (b) Ireland, J. F.; Wyatt, P. A. H. Adv. Phys. Org. Chem.
1976, 12, 131. (c) Shizuka, H.; Tobita, S. Mol. Supramol. Photochem. 2006, 14, 37.
(d) Tolbert, L. M.; Solntsev, K. M. Acc. Chem. Res. 2002, 35, 19.
(8) (a) Wan, P.; Barker, B.; Diao, L.; Fischer, M.; Shi, Y.; Yang, C. Can. J.
Chem. 1995, 74, 465. (b) Yijian, S.; Wan, P. Can. J. Chem. 2005, 83, 1306.
(9) Nakatani, K.; Higashida, N.; Saito, I. Tetrahedron Lett. 1997, 38, 5005.
(10) (a) Kostikov, A.; Popik, V. V. Org. Lett. 2008, 10, 5277. (b)
Kostikov, A.; Popik, V. V. J. Org. Chem. 2007, 72, 9190.
higher for 2-(hydroxymethyl)-4-methoxyphenol (4a, ΦFl
=
0.16 ( 0.01) than for 3a (ΦFl = 0.050 ( 0.002).12,14 This
emission hinders monitoring of laser flash-induced transfor-
mation of 3a and 4a at shorter wavelengths, but the intensity
of fluorescence dies off above 400 nm and thereby allows us
(12) See the Supporting Information.
(13) Kammerer, B.; Kahlich, R.; Biegert, C.; Gleiter, C. H.; Heide, L.
Phytochem. Anal. 2005, 16, 470–478.
(14) (a) Wang, Y.-H.; Zhang, H.-M.; Liu, L.; Liang, Z.-H.; Guo, O.-X.;
Tung, C.-H.; Inoue, Y.; Liu, Y.-C. J. Org. Chem. 2002, 67, 2429. (b) Berlman,
I. B. Handbook of Fluorescence Spectra of Aromatic Molecules; Academic
Press: New York, 1971; p 473.
(11) Arumugam, S.; Popik., V. V. J. Am. Chem. Soc. 2009, 131, 11892.
J. Org. Chem. Vol. 75, No. 21, 2010 7339

Arumugam and Popik
JOCArticle
to monitor the formation and the decay of o-QMs 1 and 2 at
wavelengths >400 nm.
SCHEME 3
Prolonged irradiation of an aqueous solution of o-QM
precursor 3a (pH 6.96 ( 0.06) with 300 nm light yielded
methyl-p-benzoquinone 5 as the only photoproduct. The
quantum yield of the formation of 5 is Φ3a = 0.060 ( 0.005.
Since competing hydration of the o-QM 1 regenerates the
starting material 3a and thus is undetectable, we have explored
the aqueous photochemistry of the corresponding ethyl ether
3b. Low conversion (∼15%) photolysis of 3b in aqueous
biphosphate buffer solutions at pH 6.96 ( 0.06 yielded diol
3a as the major product (76((2)%) and 2-methyl-1,4-benzo-
quinone (5) as the minor product (19((2)%) with quantum
efficiency Φ3b = 0.31 ( 0.01 (Scheme 2, Table 1).
This observation suggests that the secondary photoproducts are
most likely o-QM oligomers, which are trapped on the column.15
o-Hydroxybenzyltrimethylammonium salts are also known
to generate o-QMs upon irradiation.16 To compare the reactiv-
ity of o-QM generated from an alternative source, we have
studied the photochemistry of (2,5-dihydroxybenzyl)trimethyl-
ammonium iodide (3c) and (2-hydroxy-5-methoxybenzyl)tri-
methylammonium iodide (4c). 300 nm irradiation of the
ammonium salt 4c in aqueous solution cleanly produces the diol
4a. As in the case of ethyl ether 4b, low conversion photolysis of
4c gave a quantitative yield of the product, while at high con-
version the yield dropped to 76% without formation of detect-
able byproduct (Table 1). Irradiation of 3c in aqueous bipho-
sphate buffer solutions at pH 7.0 yielded both diol 3a and
p-quinone 5. The ratio of hydration to ketonization products
was similar to that obtained in the photolysis of the ether 3b
(Table 1). This observation provides additional support for the
mechanism of formation of 3a and 5 from o-QM 1.
SCHEME 2
TABLE 1. Photolysis of o-QM precursors 3a-c and 4b,c in Aqueous
Biphosphate Buffer Solutions (pH 6.96 ( 0.6)
It is interesting to note that the ratio of hydration to
ketonization products (3a/5) depends on the acidity of the
solution. Thus, diol 3a is the major product of the photolysis
of 3b at neutral pH (Table 1) and in aqueous perchloric acid
at or below 10-3 M concentration (Table 2). At higher
acidities, ketonization to produce p-quinone 5 becomes the
predominant pathway of o-QM 1 decay. o-QM 2 in aqueous
solutions produces only diol 4a irrespective of the media
acidity. No new products were detected in the photolyses of
3b and 4b in perchloric acid solutions.
o-QM
yield of 3a or
yield of 5/%
yield of 6 or
precursor 4a/% (conversion)a,b (conversion)a,b 7/% (conversion)a,c,d
3a
3b
N/A
96 ( 2 (10%)
19 ( 2 (15%)
59 ( 2 (81%)
22 ( 2 (15%)
57 ( 2 (81%)
94 ( 1 (93%)
93 ( 1 (99%)
76 ( 2 (15%)
31 ( 2 (81%)
72 ( 1 (12%)
37 ( 3 (75%)
94 ( 3 (16%)
73 ( 3 (80%)
96 ( 2 (15%)
76 ( 3 (82%)
3c
4b
4c
95 ( 1 (98%)
92 ( 2 (98%)
96 ( 1 (99%)
e
-
e
-
aλirr = 300 nm. bCa. 3 ꢀ 10-4 M in water. cCa. 3 ꢀ 10-4 M solutions of
the substrate; ca. 0.03 M ethyl vinyl ether. dIn 50% CH3CNaq
detected.
.
eNot
TABLE 2. Photolysis of 3b and 4b in Aqueous Perchloric Acid Solutions
o-QM
precursor
yield of 3a or
4a/% (conversion)
yield of 5/%
(conversion)
[HClO4]/M
At higher conversion, the chemical yield of 5 increases as the
primary product, diol 3a, is also photoactive. The chemical
yields of the products upon 300 nm irradiation of 3b are near
quantitative (∼90%) even at higher conversion (>80%) as the
benzoquinone product 5 does not have significant absorption at
the irradiation wavelength (Table 1).
3b
3b
3b
3b
4b
4b
0.001
0.01
0.05
0.1
0.001
0.1
64 ( 2 (20%)
34 ( 2 (20%)
23 ( 2 (22%)
15 ( 1 (21%)
94 ( 3 (15%)
92 ( 3 (11%)
34 ( 2 (20%)
63 ( 2 (20%)
75 ( 2 (22%)
80 ( 2 (21%)
not detected
not detected
Photolysis of aqueous solutions of o-QM precursor 4a with
300 nm light did not produce any detectable amounts of new
products due to the rapid and efficient rehydration of QM 2 to
yield back the starting material. On the other hand, irradiation of
the aqueous solution of ethyl ether 4b resulted in a rapid con-
sumption of the substrates and the formation of 4a (Scheme 3).
The quantum yield for the photoelimination of ethanol from
4b at 300 nm is Φ4b=0.28 ( 0.01.12 The chemical yield of 4a pro-
duced in this reaction is almost quantitative at low conversions,
but is somewhat reduced at longer irradiation times, apparently
due to secondary photochemical processes (Table 1). However,
no new photoproducts were detected by HPLC or isolated by
flash chromatography, even after prolonged irradiation of 4a.
Significant difference in electrophilicity between o-QMs 1and
2 becomes evident when these species are generated in aqueous
acetate buffer. Photolysis of 3b in aqueous 0.1 M acetate buffer
(pH 4.57 ( 0.05) produced the same products as in biphosphate
buffer solutions, i.e., diol 3a and p-quinone 5. The product ratio,
however, is reversed and 5 is a major product (Table 3). No
detectable amounts of new products were observed. Irradia-
tion of ether 4b under the same conditions, on the other hand,
produced substantial yield of 2-(acetoxymethyl)-4-methoxyphe-
nol (4d, Scheme 3, Table 3). The latter is apparently formed by
the attack of acetate ion on the electron-deficient methide car-
bon atom. Similar reactivity was also observed in the case of the
parent o-QM.17
(15) (a) Itoh, T. Prog. Polym. Sci. 2001, 26, 1019. (b) Dolenc, J.; Sket, B.;
Strlic, M. Tetrahedron Lett. 2002, 43, 5669.
(16) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem.
2001, 66, 41.
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Arumugam and Popik
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FIGURE 3. Transient spectra obtained at 5 μs (dashed line) and 1 ms (solid line) after the laser pulse in photolysis of ca. 0.1 mM aqueous
solutions of 3a (A) and 4a (B) at pH 7.0.
TABLE 3. Photolysis of o-QM Precursors 3b and 4b in Aqueous
Acetate Ion Buffer Solutions (0.1M buffer, pH 4.57( 0.05)
sients, which were subsequently identified as o-QMs 1and 2(vide
infra), decay at a relatively slower rate (τ = 3-8 ms). Since the
formation and the decay of o-QMs proceed at very different
rates, these processes were recorded in separate experiments with
use of different time scales and signal amplifications. The experi-
mental data were fitted separately for each transient to a double
exponential function (Figure 4) and the first order rate constants
were determined from the corresponding decay curve.12
QM
precursor
yield of 3a or
4a/% (conversion)a
yield of 4d/%
(conversion)a
yield of 5/%
(conversion)a
3b
27 ( 2 (29%)
no acetylation
product
70 ( 2 (29%)
4b
66 ( 2 (13%)
31 ( 2 (13%)
not detected
aλirr = 300 nm; ca. 3 ꢀ 10-4 M in water.
Quinone methides are known to undergo very efficient
hetero-Diels-Alder reactions with electron-rich alkenes.4
Irradiation of 3a and 4a in aqueous acetonitrile in the
presence of 30 mM ethyl vinyl ether resulted in the formation
of adducts 6 and 7 in 90% isolated yields (Scheme 4).12
SCHEME 4
HPLC analysis shows near-quantitative formation of vinyl
ether adducts in photolysis of alternative o-QM precursors 3b,c
and 4b,cat both high and low conversions (Table 1). Products of
o-QM hydration (3a and 4a) or ketonization (5) were not
detected in these experiments. The exclusive formation of
Diels-Alder adduct despite the presence of more than a thou-
sand-fold excess (33 M versus 0.03 M) of a nucleophilic solvent
indicates that addition of ethyl vinyl ether to o-QMs is more than
2 orders of magnitude faster than a hydration reaction. Direct
kinetic measurements of the rate of o-QM 1 and 2 reaction with
ethyl vinyl ether were precluded by strong absorbance of 266 nm
laser pulse by the alkene under experimental conditions ([QM
precursor] = 10-4 M; [vinyl ether] = 0.02-0.1M).
Kinetics of the Formation and Reactions of 4-Hydroxy-6-
methylene-2,4-cyclohexadien-1-one (1) and 4-Methoxy-6-
methylene-2,4-cyclohexadien-1-one (2). Rate measurements
were conducted in aqueous solutions at 25 ( 0.1 °C and ca. 10-4
M concentration of a substrate. Excitation of diols 3a and 4a
with 4 ns 266 nm pulses of a Nd:YAG laser under these con-
ditions results in the formation of short-lived transients
(τ ≈ 20 μs) with λmax ≈ 410 nm, which rapidly decay to yield new
intermediates with λmax ≈ 420 nm (Figure 3). The latter tran-
FIGURE 4. Formation and decay of o-QM 1 in the flash photolysis
of ca. 0.1 mM aqueous solution of 3a at pH 7.0.
The identity of the longer lived transients was established on
the basis of their reactivity toward nucleophiles. Thus, decay of
the second transients in wholly aqueous solution is relatively
slow: kobs(3a)=300 ( 5s-1 at pH 7.0; and kobs(4a)=126 (4 s-1
at pH 7.0. Addition of the azide ion dramatically increases
the rate of this process: kN3(3a) = 3.30 ꢀ 104 M-1 s-1; and
kN3(4a)=3.15 ꢀ 104 M-1 s-1 (Figure 5). On the other hand, the
lifetime of the first transients generated from 3a and 4a was not
affected by the presence of azide anion. Azide anion was pre-
viously demonstrated to increase the decay rate of o-QMs due to
their pronounced electrophilicity.11,18 Additional support for
the structural assignments of the second transients came from
the results of the laser flash photolyses of 2,5-dihydroxybenzyl-
trimethylammonium iodide 3c and 2-hydroxy-5-methoxyben-
zyltrimethylammonium iodide 4c. Photochemical decompo-
sition of 3c and 4c produces the same set of products as the
(18) Richard, J. P.; Amyes, T. L.; Bei, L.; Stubblefield, V. J. Am. Chem.
Soc. 1990, 112, 9513.
(17) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123, 8089.
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Arumugam and Popik
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FIGURE 5. Quenching of o-QM 1 triangles) and 2 (circles) by
sodium azide in aqueous solutions at pH 7.0.
FIGURE 6. Rate profile for the hydration of o-QM 1 (solid squares)
and 2 (open circles) in aqueous solution at 25 °C.
photolyses of 3a,b and 4a,b, which are produced from o-QMs 1
and 2. However, only a single transient is observed in laser flash
photolysis of ammonium salts 3c or 4c. The spectral properties,
lifetime, and reactivity of these intermediates are identical,
within the uncertainty limits, to that of the second transient
generated from 3a and 4a.
Kinetics of Decay of o-QMs 1 and 2 in Aqueous Perchloric
Acid, Sodium Hydroxide, and Buffer Solutions. Rates of the
decay of o-QM 1 and 2 were determined in dilute aqueous
solutions of perchloric acid and sodium hydroxide, as well as
biphosphate ion, bicarbonate ion, and acetic acid buffers.
The ionic strength of these solutions was kept constant at
0.1 M by adding sodium perchlorate as required. The rates of
decay of the first transient observed in photolyses of 3a and
4a remain constant through the entire pH range. The decay
of second transients, o-QMs 1 and 2, on the other hand, is
catalyzed by by perchloric acid, hydroxide ion, as well as
some buffers (vide infra). Kinetic measurements in buffered
solutions were performed in a series of solutions of varying
buffer concentration but constant buffer ratio. The observed
rates were then extrapolated to a zero buffer concentration.
Relatively strong buffer catalysis was observed for the decay
of both o-QMs 1 and 2 in acetate buffer solutions. However,
only the rate of decay of o-QM 1 shows appreciable buffer
catalysis in phosphate and bicarbonate buffer solutions.
While the buffer catalysis for the decay of QM 2 in phosphate
and bicarbonate buffer solution was very weak, the zero-
concentration intercepts for the rate of decay of QM 2 were
well-determined. The buffer-independent rate constants,
together with observed rate constants determined in per-
chloric acid and sodium hydroxide solutions, are shown as
the rate profile in Figure 6.
FIGURE 7. Specific acid catalysis observed of o-QMs 1 (triangles)
and 2 (circles) generated from 3c and 4 in aqueous perchloric acid.
transient observed in the photolyses of ammonium salts 3c
(kHþ = (8.12 ( 0.10) ꢀ 103 M-1 s-1) and 4c (kHþ = (3.49 (
0.07) ꢀ 104 M-1 s-1) is very similar to that of o-QMs
generated from the diols 3a and 4a. This further confirms
that the second transients observed in laser flash photolysis
of 3a and 4a are indeed the o-QMs 1 and 2, respectively. As in
the case of the parent o-QM,4b,19 the observed specific acid
catalysis can be attributed to the rapid equilibration between
o-QMs and more electrophilic o-hydroxybenzyl cations 1þ
and 2þ (Scheme 5). The specific acid catalysis of the o-QM 2
hydration is somewhat weaker than that observed for the
parent benzene-1,2-quinone methide (kHþ = 8.4 ꢀ 105 M-1
s-1),4b,17 apparently due to the presence of the electron-rich
methoxy group. Similar reduction of the electrophilicity
of methide carbon by m-methoxy substitution was observed
on addition of various nucleophiles to o-QMs.5d Electron-
donating abilities of hydroxy and methoxy groups are close
but acid catalysis of o-QM 1 decay is stronger than that of 2.
The higher acid sensitivity of 1 indicates that both hydration
and ketonization reactions of this o-QM are catalyzed by
acid. In fact, the 5 to 3a ratio increases at higher hydronium
ion concentration apparently due to stronger acid catalysis
of the ketonization reaction (Table 2).
The rate of hydration of o-QMs 1 and 2 is independent of
the acidity of aqueous solutions in the range from pH 4 to 10
resulting in a broad horizontal region in the rate profile
(Figure 6). The observed rate constants on the plateau are
kH O = 300 ( 27 s-1 for o-QM 1 and kH O = 126 ( 16 s-1 for
2
2
o-QM 2. The lower uncatalyzed hydration rate of o-QM 2 in
comparison with the parent o-QM (kH O = 260 s-1 17
)
is
2
apparently due to its reduced electrophilicty. In the case of
o-QM 1 the lower rate of hydration is apparently augmented
by the ketonization reaction. The decay rates of o-QMs 1 and
2 rise in a linear proportion to acid concentration: kHþ(1) =
(8.37 ( 0.16) ꢀ 103 M-1 s-1; kHþ(2) = (3.30 ( 0.01) ꢀ 104
M-1 s-1 (Figure 7). The acid catalysis of the decay of the only
The decay of o-QMs 1 and 2 is also strongly catalyzed by
the hydroxide ion: kOH(1) = (3.51 ( 0.19) ꢀ 104 M-1 s-1 and
(19) Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z.,
Ed.; Wiley: New York, 1990; Chapter 7.
7342 J. Org. Chem. Vol. 75, No. 21, 2010

Arumugam and Popik
JOCArticle
SCHEME 5
kOH(2)= (1.08 ( 0.02) ꢀ 104 M-1 s-1. The reactivities of
o-QMs 1 and 2 toward nucleophilic attack by the hydroxide
ion are very similar to those of the parent o-QM. However,
the rate of hydration of 2 in aqueous sodium hydroxide
solution is somewhat reduced in comparison to that of parent
quinone methide (kOH = (3.0 ꢀ 104 M-1 s-1).17 This is again
attributed to the reduced electrophilicity of this o-QM due to
electron-donating substituents in the ring.5d On the other hand,
the hydroxide ion catalysis of the decay of 1 is more than three
times stronger than that of 2. This higher reactivity is due to the
fact that the second pathway open to o-QM 1, i.e., ketonization
to 5, is also catalyzed by a specific base.
The rate profiles of Figure 6 are readily understood in
terms of the reaction Scheme 5. Thus, the major reaction
consuming o-QM 2 in aqueous solutions is hydration to 4a.
o-QM 1, on the other hand, reacts via two pathways: hydra-
tion to form 3a and ketonization to p-quinone 5 (Scheme 5).
The hydration mechanism of both o-QM 1 and 2 is very
similar to that of the parent o-QM.4b In the base-catalyzed
region of the rate profiles hydration apparently occurs via
the rate-limiting attack of the hydroxide ion on the methide
carbon of o-QMs 1 and 2. Specific acid catalysis at pH <3
should be assigned to the rapid pre-equilibrium protonation
of the o-QM, which produces the more reactive cation 1þ/2þ
(Scheme 5). The uncatalyzed portion of the rate profile at pH
between 4 and 10 has two possible interpretations. The first is
reversible protonation of the o-QMs by water, followed by rate-
determining cation capture by the hydroxide ion so formed. As
in the case of parent o-QM, this mechanism can be ruled out on
the basis of the fact that it would require an impossibly large
value of the rate constant for its rate-determining step.19 The
more probable mechanism of the pH-independent hydration is
simple nucleophilic attack of water on the o-QM methylene
group, with or without simultaneous proton transfer to avoid a
zwitterionic intermediate 8 (Scheme 5).
in Scheme 5. Rate measurements were conducted in D2O
solutions of DCl in the range of concentrations from 0.001 to
0.1 M. The kinetic solvent isotopic effect on the acid-
catalyzed hydration of 2 (kHþ/kDþ = 0.48) is very similar to
that of the parent o-QM (kHþ/kDþ = 0.42).5b Such an inverse
solvent isotopic effect is attributed to the rapid pre-equilib-
rium substrate protonation and is due to the fact that acids are
weaker in D2O and the fraction of more reactive protonated
species 2þ grows faster with Dþ concentration than with Hþ.20
The hydration reaction of 2 on the plateau region was slower in
D2O (kH O/kD O = 1.63). The nature of this isotope effect stems
2
2
from the fact that positively charged O-H bonds, such as those
in the intermediate 8 (Scheme 5), are looser than uncharged
O-H bonds, such as those in a water molecule. Conversion
þ
of H2O into ROH2 leads to a loosening of the hydrogenic
environment of the species involved, and that produces an
isotope effect in the normal direction. Since the major reaction
of the o-QM 1 within the pH 3-10 range is addition of water to
produce 3a, the observed solvent isotope effect (kH O/kD O
=
2
2
1.49) is similar to that of 2. In a sharp contrast with 2, the isotope
effect on acid-catalyzed (pH <3) reactions of 1 is in the normal
direction (kHþ/kDþ=1.60). This observation can be explained by
the fact that ketonization to methyl-p-quinone (5) becomes an
increasingly important pathway of the o-QM 1 decay at higher
acidities. The ketonization reaction, which is known to proceed
via rate-determining proton transfer, is expected to produce a
normal kinetic isotope effect (Scheme 5).20,21
Buffer Catalysis. The rate of o-QM 2 hydration shows
virtually no dependence on the concentration of phosphate
and bicarbonate buffer, resembling the behavior of the
parent o-QM.17 This observation agrees well with the nucleo-
philic hydration mechanism (Scheme 5). However, in the
acetate buffer solutions, the rate of decay of o-QM 2 shows
significant buffer catalysis. Rate measurements were per-
formed in four series of solutions of varying acetate buffer
concentrations but constant buffer ratio in each series.
Slopes of buffer dilution plots at various buffer ratios
represent pH-independent catalysis by the buffer compo-
nents. As is evident from Figure 8, the efficiency of acetate
Hydration of o-QM 1 to diol 3a is accompanied by the
tautomerization to methyl-p-quinone (5), which also shows
acid and base catalysis. Conversion of o-QM 1 to 5 is, in fact,
a vinylogous ketonization reaction. Such a process usually
proceeds via rate-limiting proton transfer on a δ-carbon of a
conjugated enol and, therefore, is catalyzed by general and
specific acids.19 Within the pH-independent part of the rate
profile water takes over as the major protonating species. At
pH >9, the fraction of o-QM 1 existing in more reactive
enolate form 9 grows with increasing pH producing an
apparent hydroxide ion catalysis (Scheme 5).
(20) 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.
(21) (a) Capon, B.; Siddhanta, A. K.; Zucco, C. J. Org. Chem. 1985, 50,
3580. (b) Chiang, Y.; Guo, H.-X.; Kresge, A. J.; Tee, O. S. J. Am. Chem. Soc.
1996, 118, 3386. (c) Chiang, Y.; Kresge, A. J.; Santaballa, J. A.; Wirz, J.
J. Am. Chem. Soc. 1988, 110, 5506. (d) Pruszynski, P.; Chiang, Y.; Kresge,
A. J.; Schepp, N. P.; Walsh, P. A. J. Phys. Chem. 1986, 90, 3760. (e) Chiang,
Y.; Kresge, A. J.; Nikolaev, V. A.; Popik, V. V J. Am. Chem. Soc. 1997, 190,
11183. (f) Capponi, M.; Gut, I. G.; Hellrung, B.; Persy, G.; Wirz, J. Can. J.
Chem. 1999, 77, 605.
Solvent isotope effects on the rate of o-QMs 1 and 2
consumption provide additional support for the mechanism
J. Org. Chem. Vol. 75, No. 21, 2010 7343

Arumugam and Popik
JOCArticle
of this mechanism will produce hydroxide ion catalysis and the
second is catalyzed by a general acid. Combination of these to
catalyses is operationally equivalent to a general base catalysis.
Elucidation of the o-QMs Precursor Structures. In agree-
ment with previous reports,4b parent o-QM is formed within
the duration of a laser pulse in the flash photolysis of o-hydroxy-
benzyl alcohol. We observed similar “instant” formation of
o-QMs 1 and 2 in photolyses of ammonium precursors 3c and
4c. In a sharp contrast with these results, laser flash photolysis of
2-(hydroxymethyl)benzene-1,4-diol (3a) and 2-(hydroxy-
methyl)-4-methoxyphenol (4a), as well as their ether analogues
3b and 4b, allowed us to detect a short-lived (τ ≈ 20 μs) kinetic
precursor to o-QMs. In unbuffered aqueous solutions o-QM 1 is
produced with the observed rate k=(4.80(0.20) ꢀ 104 s-1 and
o-QM 2 with kobs = (5.00 ( 0.45) ꢀ 104 s-1. The rate of o-QMs
formation is independent of pH of the solution and is not
affected by the presence of the azide ion. The fluorescence
lifetimes of 3a and 4a (τ ≈ 8 ns) are much shorter than the rise
time of the corresponding o-QMs, indicating that the latter
species are not formed directly from the singlet excited state of
the diol precursors. Saturation of the solution with oxygen or
addition of increased amounts 1,3-cyclohexadiene to the reac-
tion mixture before the photolysis do not quench the first
transient or affect the rate of its decay. This observation allows
us to conclude that triple excited states of 3a and 4a are not
involved in the formation of the respective o-QMs. The zwitter-
ionic structure 8, which can be potentially formed in ESIPT to
benzylic oxygen atom in 3a or 4a (Scheme 6), is an unlikely
candidate for o-QM precursor because reverse proton transfer in
this structure should proceed at least at the diffusion-controlled
rate limit. In fact, pH insensitivity of the first transient allows us
to exclude all ionized forms of 3a and 4a from consideration.
FIGURE 8. Dependence of the acetate buffer catalysis of o-QM 2
decay on the fraction of free acid in the buffer.
FIGURE 9. Dependence of the buffer catalysis of the decay of
o-QM 1 on the fraction of free acid in the buffer.
SCHEME 6
buffer catalysis decreases with increased fraction of free acid.
This observation, as well as the observed formation of
acetylation product 4d (Scheme 3, Table 3), indicate the
nucleophilic nature of the acetate buffer catalysis of o-QM 2
hydration. Similar reactivity was also observed in the case of
the parent o-QM.17
In a contrast to o-QM 2, the rate decay of o-QM 1 is more
sensitive to the free acid concentration in both phosphate and
acetate buffer solutions (Figure 9). The strong buffer catalysis of
the decay of o-QM 1 observed in all buffers examined can be
explained by the fact that the ketonization reactions are usually
catalyzed by general acid (Scheme 5).22 Thus, in 0.1 M acetate
buffer o-QM 1 does not form any detectable amounts of new
products, but the ratio of ketonization to hydration products
increases dramatically (Table 3). Buffer catalytic coefficients
can be partitioned into contributions from the acidic and basic
components by extrapolation of the plots in Figure 9 to fA = 1
ESIPT from the phenolic oxygen to the aromatic carbon is
well documented for phenols and naphthols.22 Such carbon
protonation leading to the unstable keto-form of phenol (such as
10, Scheme 5, or its isomers) should result in incorporation of
deuterium in hydration products when photolysis is conducted
in deutrated solvents. GC-MS analysis of the products formed
after prolonged irradiation of diols 3a and 4a in D2O showed no
deuterium enrichment in the aromatic rings. This observation
allows us to rule out participation of 10 or isomeric structures. It
has been shown, on the other hand, that o-quinone methides
might reversibly isomerize to benzoxete derivatives, which are
stable only at cryogenic temperatures.23 A similar ring-opening
reaction is actually used for the generation of thio-o-quinone
methides from benzothietes.24 We have recently reported
(general acid: kH PO - = (1.99 ( 0.02) ꢀ 103 M-1 s-1; kHOAc
=
2
4
(4.20 ( 0.11) ꢀ 103 M-1 s-1) and fA = 0 (general base catalysis:
kHPO 2- = (7.40 (0.02) ꢀ 102 M-1 s-1;kAcO- = (1.44 (0.05) ꢀ
4 -1
(23) (a) Qiao, G. G.; Lenghaus, K.; Solomon, D. H.; Reisinger, A.;
Bytheway, I.; Wentrup, C. J. Org. Chem. 1998, 63, 9806. (b) Tomioka, H.
Pure Appl. Chem. 1997, 69, 837. (c) Sauter, M.; Adam, W. Acc. Chem. Res.
1995, 28, 289. (d) Shanks, D.; Frisell, H.; Ottosson, H.; Engman, L. Org.
Biomol. Chem. 2006, 4, 846.
103 M s-1). Ketonization reaction in buffer solutions can also
occur by ionization of o-QM 2 to the enolate ion 9 followed by
the proton transfer from the buffer acid (Scheme 5). The first step
(24) (a) Mayer, A.; Meier, H. Tetrahedron Lett. 1994, 35, 2161. (b) Meier,
H.; Mayer, A.; Groschl, D. Sulfur Rep. 1994, 16, 23 and references cited
therein. (c) Meier, H.; Eckes, H.-L.; Niedermann, H.-P.; Kolshorn, H.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1046. (d) Kanakarajan, K.; Meier,
H. J. Org. Chem. 1983, 48, 881.
(22) (a) Lukeman, M.; Wan, P. J. Am. Chem. Soc. 2003, 125, 1164. (b)
Lukeman, M.; Veale, D.; Wan, P.; Munasinghe, V. R. N.; Corrie, J. E. T.
Can. J. Chem. 2004, 82, 240. (c) Basaric, N.; Wan, P. J. Org. Chem. 2006, 71,
2677.
7344 J. Org. Chem. Vol. 75, No. 21, 2010

Arumugam and Popik
JOCArticle
SCHEME 7
Solutions of ca. 3 ꢀ 10-4 M of compounds 3b, 3c, 4b, and 4c
were irradiated in water and in the presence of ethyl vinyl ether
(3 ꢀ 10-2 M) in 50% MeCN in water, using a mini-Rayonet
photochemical reactor equipped with eight fluorescent UV
lamps (4 W, 300 nm). Reaction mixtures after photolysis were
analyzed by HPLC and chemical yields were determined from
the calibration plot constructed with known standards of the
pure product. Quantum efficiencies of photochemical reactions
were measured by ferrioxalate actinometry.26 Buffer solutions
for kinetic experiments were prepared by using literature pKa
values of the buffer acids and activity coefficient recommended
by Bates.27
the detection of naphthoxete precursors of naphthoquinone
methides.11 We, therefore, believe that oxetanes 11 and 12 are
the likely precursors of o-QMs 1 and 2 (Scheme 7).
Kinetic Experiments. Rate measurements were conducted
with a nanosecond kinetic spectrometer equipped with a Nd:
YAG laser (pulse width = 4 ns) fitted with second and fourth
harmonic generators. Degassed solutions of o-QM precursors
with OD ≈ 0.4 were thermostated at 25 ( 0.05 °C. Since the
formation and the decay of o-QMs proceed at very different
rates, these processes were recorded in separate experiments
with different time scales and signal amplifications. The experi-
mental data were fitted separately for each transient to a double
exponential function and the first order rate constants were
determined from the corresponding decay curve. Second order
rate constant of o-QM reactions with azide ion were determined
from the plot of the concentration of the trapping reagents vs the
observed pseudo-first-order rate constants. The experimental
rate constants are summarized in Tables S1-S20 in the Sup-
porting Information.12
Since the fluorescence spectra of 3a and 4a are very similar
to spectra of corresponding phenols,25 we can assume that
excitation of these substrates results in the formation of the
phenolate ions in the excited state. If the o-benzylic position
þ
is substituted with a good leaving group (e.g., X = NMe3
,
Scheme 7), the o-QM is formed directly from the phenolate
ion. However, in case of poor leaving groups (e.g., X = OH
or OR), oxetane is formed. The latter then opens up in a
ground state reaction to give an o-QM. Ring-opening of 11
and 12 to give o-QMs 1 and 2 is an electrocyclic reaction and,
therefore, is not sensitive to acid/base catalysis or the pre-
sence of reactive nucleophiles such as azide ion.
Conclusions
Fluorescent Measurements. Fluorescent spectra of 3a and 4a
were recorded at λex = 305 nm in doubly deionized water with
the substrate concentration ca. 1 ꢀ 10-5 M, using Varian steady
state fluorimeter. The excitation source slits and the detector
slits were set to 2 and 5 nm, respectively. The fluorescence
quantum yields were determined with phenol as the standard
reference.27,28
Materials. Ethyl vinyl ether and sodium were purchased from
Sigma-Aldrich and used as received. 2-(Hydroxymethyl)benzene-
1,4-diol (3a),29 (2-(hydroxymethyl)-4-methoxyphenol (4a),30 (2-
hydroxy-5-methoxy-1-phenyl)methyltrimethylammonium iodide
(4c),5d and 2-(acetoxymethyl)-4-methoxyphenol (4d)31 were pre-
pared following the literature procedures.
Two o-quinone methides, 4-hydroxy-6-methylene-2,4-cy-
clohexadien-1-one (1) and 4-methoxy-6-methylene-2,4-cy-
clohexadien-1-one (2), are efficiently generated by the
irradiation of three different types of precursors: substituted
o-hydroxybenzyl alcohols 3a and 4a; their ethyl ethers 3b and
4b, as well as (2,5-dihydroxy-1-phenyl)methyl- (3c) and (2-
hydroxy-5-methoxy-1-phenyl)methyltrimethylammonium
iodides (4c). The reactivity of o-QMs 2 resembles that of
other o-quinone methides albeit with reduced nucleophili-
city. In aqueous solution it undergoes efficient rehydration
back to 4a and this reaction is catalyzed by both hydroxide
and hydronium ions. In the case of o-QMs 1, addition of
water to give 3a competes with tautomerization to form
methyl-p-quinone (5). This is a rather unique phenomenon,
as the same carbon atom shows both electrophilic (addition
of water) and nucleophilic (protonation) reactivity. The
ketonization reaction shows pronounced general acid cata-
lysis. Both o-QMs readily react with other nucleophiles such
as azide anion and undergo efficient Diels-Alder cycloaddi-
tion to electron-rich olefins. Photochemical dehydration of
3a and 4a to produce o-QMs 1 and 2 proceeds via the
formation of a reactive intermediate. On the basis of the
reactivity of these transient species the benzoxete structures
11 and 12 were assigned to these transients.
2-(Ethoxymethyl)benzene-1,4-diol (3b). A solution of 3a
(70 mg, 1 mmol) in 80% aqueous ethanol (500 mL) was irradiated,
using a mini-Rayonet photochemical reactor equipped with
254 nm lamps for 1 h. Photolysate was extracted with ethyl acetate
then dried over sodium sulfate; solvents were removed under
vacuum. The residue was separated by chromatography (30%
EtOAc in hexane) to give 50 mg (60%) of 3b as a colorless oil. 1H
NMR δ 6.72-6.74 (m, 1H), 6.65-6.67 (m, 1H), 6.52-6.53 (m,
1H), 4.61 (s, 2H), 3.60 (q, 2H, J = 5.2 Hz), 1.26 (t, 3H, 5.2 Hz). 13
C
NMR δ 149.8, 148.9, 123.4, 117.3, 116.1, 115.1, 71.9, 66.5, 15.2;
GC-MS m/z (%) 168 (10), 138 (100), 137 (40), 122 (60), 121 (25),
110 (65), 94 (50), 82 (37), 63 (45), 53 (47). FW calcd for C9H12O3
þ
168.0786; EI-HRMS found 168.0783.
2-(Ethoxymethyl)-4-methoxyphenol (4b). Concentrated HCl
(5 mL) was added to a solution of 4a (500 mg, 3.25 mmol) in 95%
aqueous ethanol (20 mL), then the reaction mixture was stirred
Experimental Section
General Methods. All organic solvents were dried and freshly
distilled before use. Flash chromatography was performed with
40-63 μm silica gel. All NMR spectra were recorded in CDCl3
and referenced to TMS unless otherwise noted. Solutions were
prepared with HPLC grade water, methanol, and acetonitrile.
Substrate concentration for kinetics experiments was kept at ca.
1 ꢀ 10-4 M for 3a and 4a and 5 ꢀ 10-5 M for 3c and 4c.
(26) Murov, S. L.; Carmichael, I.; Hug, G. L. In Handbook of Photo-
chemistry; Marcel Dekker: New York, 1993; p 299.
(27) Bates, R. G. Determination of pH Theory and Practice; Wiley: New York,
1973; p 49.
(28) Berlman, I. B. Handbook of Fluorescence Spectra of Aromatic
Molecules; Academic Press: New York, 1971; p 473.
(29) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G. Synthesis 1980, 2,
124.
(30) Ono, M.; Kawashima, H.; Nonaka, A.; Kawai, T.; Haratake, M.;
Mori, H.; Kung, M. P.; Kung, H. F.; Saji, H.; Nakayama, M. J. Med. Chem.
2006, 49, 2725.
(25) (a) Wehry, E. L.; Rogers, L. B. J. Am. Chem. Soc. 1965, 87, 4234.
(b) Stalin, T.; Devi, R. A.; Rajendiran, N. Spectrochim. Acta 2005, 61A, 2495.
(31) Bray, C. D. Synlett 2008, 16, 2500.
J. Org. Chem. Vol. 75, No. 21, 2010 7345

Arumugam and Popik
JOCArticle
for 3 h at rt and poured onto crushed ice. The aqueous layer was
extracted with ethyl acetate and dried over sodium sulfate;
solvents were removed under vacuum. The crude product was
purified by column chromatography (40% dichloromethane in
hexane) to give 4b as a yellow oil (366 mg, 62%). 1H NMR δ 7.27
(br s, 1H), 6.72-6.80 (m, 2H), 6.56-6.57 (m, 1H), 4.64 (s, 2H),
137 (52), 136 (40), 123 (12), 108 (17), 94 (12), 73 (17), 70 (37), 6þ1
(50), 53 (27), 44 (62), 45 (100). FW calcd for C10H16NO2
182.1181; EI-HRMS found 182.1188.
2-Ethoxy-6-hydroxychroman (6). A solution of 3a (42 mg, 0.3
mmol) and ethyl vinyl ether (2.9 mL, 30 mmol) in aqueous
acetonitrile (1:1, 300 mL) was irradiated, using a mini-Rayonet
photochemical reactor equipped with 254 nm lamps for 1 h.
Photolysate was extracted with ethyl acetate and dried over
sodium sulfate; solvents were removed under vacuum. The
residue was separated by chromatography (20% EtOAc in
3.72 (s, 3H), 3.58 (q, 2H, J = 5.2 Hz), 1.25 (t, 3H, 5.2 Hz). 13
C
NMR δ 153.2, 150.3, 123.3, 117.3, 114.5, 113.9, 72.3, 66.5, 56.0,
15.3. GC-MS m/z (%) 182 (20), 136 (100), 137 (20), 108 (45), 79
(20), 65 (20). FW calcd for C10H14O3 182.0943; EI-HRMS
þ
1
found 182.0943.
hexane) to give 53 mg (90%) of 6 as a colorless oil. H NMR
(2,5-Dihydroxy-1-phenyl)methyltrimethylammonium Iodide
(3c). A solution of 2,4-dihydroxybenzaldehyde (900 mg, 6.67
mmol) in methanol (15 mL) was added to a mixture of 1.16 g
(14.2 mmol) of dimethylamine hydrochloride, sodium acetate
(0.91 g, 11.1 mmol), and 0.49 g (7.7 mmol) of sodium cyanobor-
ohydride in methanol (30 mL).The pH of the solution was
maintained throughout the reaction in the range 7-8 by the
addition of concentrated HCl. The solution was stirred at room
temperature during 24 h. Acetone (50 mL) was added and the
solution was acidified to pH 2-3 with 6 N HCl solution.
Solvents were removed under vacuum, and the residue was
redissolved in water (15 mL) and washed with ether (4 ꢀ 15
mL). NaOH solution was added to the remaining aqueous phase
until pH reached 8-9. The resulting aqueous solution was
extracted with ether (6 ꢀ 25 mL), the organic layer was dried
over MgSO4, and solvent was removed under vacuum. The
fractional distillation of amber oil residue produced 0.8 g of pure
2-(N,N-dimethylaminomethyl)benzene-1,4-diol (71% yield) as
(400 MHz, CDCl3) δ 6.69-6.70 (m, 1H), 6.53-6.60 (m, 2H),
5.20 (t, 1H, J = 2.8 Hz), 3.82-3.88 (m, 1H), 3.59-3-64 (m,
1H), 2.88-2.97 (m, 1H), 2.60, 2.55-2.59 (m, 1H), 1.88-2.03 (m,
2H), 1.18 (t, 3H, 7.6 Hz). 13C NMR (100 MHz, CDCl3) δ 149.3,
146.3, 123.71, 117.8, 115.6, 114.5, 96.9, 63.8, 26.7, 20.9, 15.3. GC
MS m/z 195 (10), 194 (90), 149 (30), 148 (70), 147 (100), 122 (50),
94 (30), 77 (20), 65 (25), 55 (28), 45 (15). FW calcd for C11H14O3
194.0943, EI-HRMS found 194.0952.
2-Ethoxy-6-methoxychroman (7). Compound 7 was prepared
in 91% yield following the same procedure that was described
for 6. The spectral properties are consistent with the previously
reported values.32 1H NMR (400 MHz, CDCl3) δ 6.69-6.78(m,
2H), 6.61-6.62 (m, 1H), 5.23 (t, 1H, J = 2.8 Hz), 3.84-3.90 (m,
1H), 3.76 (s, 3H), 3.60-3-66 (m, 1H), 2.94-3.02 (m, 1H),
2.60-2.66 (m, 2H), 1.90-2.07 (m, 2H), 1.20 (t, 3H, J = 7.6
Hz). 13C NMR of 2 (100 MHz, CDCl3) δ 153.8, 146.3, 123.5,
117.7, 114.1, 113.5, 97.0, 63.8, 55.9, 26.8, 21.2, 15.4. GC MS m/z
208 (100), 180 (5), 163 (30), 162 (35), 161 (40), 147 (8), 136 (75),
108 (27), 91 (12), 73 (12), 65 (12), 55 (7), 43 (5). FW calcd for
C12H16O3 208.1099, EI-HRMS found 208.1102.
1
a colorless oil. H NMR (400 MHz, CDCl3) δ 6.62-6.50 (m,
3H), 3.54 (s, 2H), 2.28 (s, 6H). 13C NMR (100 MHz, CDCl3)
δ 151.1, 149.9, 123.0, 116.1, 115.4, 115.0, 62.6, 43.9. GC-MS
m/z (%) 168 (10), 167 (45), 152 (6), 122 (12), 94 (15), 58 (25),
44 (100).
Acknowledgment. The authors thank the National
Science Foundation (CHE-0449478) and the donors of the
ACS Petroleum Research Fund (434444-AC4) for the sup-
port of this project.
Methyl iodide (1.5 mL) was added to a stirred solution (0 °C)
of 2-(N,N-dimethylaminomethyl)benzene-1,4-diol (450 mg, 2.5
mmol) in acetonitrile (1.5 mL) and the mixture was stirred for 2 h
at rt. Anhydrous ether (25 mL) was added to the reaction
mixture, and white precipitate separated and was washed with
ether to give 0.8 g (98%) of quaternary ammonium salt 3c as a
Supporting Information Available: Tables of raw kinetic
measurements and NMR spectra of newly synthesized com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
white solid. H NMR (400 MHz, D2O) δ 6.78-6.86 (m, 3H),
4.29 (s, 2H), 3.63 (s, 3H), 2.99 (s, 9H). 13C NMR (100 MHz,
D2O) δ 150.0, 148.7, 120.6, 119.7, 117.8, 115.4, 64.1, 52.7. GC-
MS m/z (%) 182 (7), 181 (45), 168 (10), 168 (5), 167 (30), 149 (8),
(32) Manetsch, R.; Zheng, L.; Reymond, M. T.; Woggon, W.-D.; Reymond,
J.-L. Chem.;Eur. J. 2004, 10, 2487.
7346 J. Org. Chem. Vol. 75, No. 21, 2010