Photochemical generation and the reactivity of o-naphthoquinone methides in aqueous solutions

Article abstract of DOI:10.1021/ja9031924

Irradiation of 3-hydroxy-2-naphthalenemethanol (3a) and 2-hydroxy-1-naphthalenemethanol (4a) results in efficient (Φ₂₅₄ ) 0.17 and 0.20) dehydration and the formation of isomeric naphthoquinone methides, 2,3-naphthoquinone-3-methide (1) and 1,2

Full text of DOI:10.1021/ja9031924

Published on Web 08/03/2009
Photochemical Generation and the Reactivity of
o-Naphthoquinone Methides in Aqueous Solutions
Selvanathan Arumugam and Vladimir V. Popik*
Department of Chemistry, UniVersity of Georgia, Athens, Georgia, 30602
Received April 29, 2009; E-mail: vpopik@chem.uga.edu
Abstract: Irradiation of 3-hydroxy-2-naphthalenemethanol (3a) and 2-hydroxy-1-naphthalenemethanol (4a)
results in efficient (Φ254 ) 0.17 and 0.20) dehydration and the formation of isomeric naphthoquinone
methides, 2,3-naphthoquinone-3-methide (1) and 1,2-naphthoquinone-1-methide (2), respectively. In
aqueous solution, naphthoquinone methides 1 and 2 undergo rapid hydration to regenerate starting materials
(τH2O (1) ) 7.4 ms and τH2O (2) ) 4.5 ms at 25 °C). The hydration reaction is strongly catalyzed by the
hydroxide ion but shows acid catalysis only at pH < 1. Reactive intermediates 1 and 2 can be intercepted
by other nucleophiles, such as the azide ion (kN3(1) ) 2.0 × 104 M-1 s-1 and kN3(2) ) 3.0 × 104 M-1 s-1
)
or thiol (kSH(1) ) 2.2 × 105 M-1 s-1 and kSH(2) ) 3.3 × 105 M-1 s-1). Ethyl vinyl ether readily reacts with
1 and 2 (kDA(1) ) 4.1 × 104 M-1 s-1 and kDA(2) ) 6.0 × 104 M-1 s-1) to produce Diels-Alder adducts in
excellent yield. o-Naphthoquinone methides 1 and 2 were also generated by photolysis of 3-ethoxymethyl-
(3b) and 1-(ethoxymethyl)-2-naphthols (4b), as well as from (2-hydroxy-3-naphthyl)methyl- (3c) and [(2-
hydroxy-1-naphthyl)methyl] trimethylammonium iodides (4c). Laser flash photolysis of 3a,b and 4a,b allows
the detection of short-lived (τ25°C ∼ 12 µs) precursors of naphthoquinone methides 1 and 2. On the basis
of the precursor reactivity and the results of DFT calculations, 2H-naphthoxete structure was assigned to
these species.
families.4 The reactivity of oQMs resembles that of R,ꢀ-
unsaturated ketones. The zwitterionic resonance form in the
Introduction
o-Quinone methides (oQMs) are important intermediates in
former, however, is additionally stabilized by aromatic conjuga-
tion (Scheme 1). Enhanced charge separation results in high
electrophilicity of the methide carbon atom, and also makes
Diels-Alder addition of electron-rich alkenes to oQMs very
facile.5
many chemical and biological processes.1,2 These reactive
species are efficient dDNA alkylating and cross-linking agents,3
and are believed to be responsible for the cytotoxicity of
antitumor antibiotics of the mitomycin C and anthracycline
oQMs can be conveniently generated by photochemical
dehydration of o-hydroxybenzyl alcohols and its analogues
(Scheme 1).1a,5a-c The loss of water from the excited state of
o-hydroxybenzyl alcohols is very fast and the formation of
oQMs is usually complete within a nanosecond laser pulse.5a-c
The mechanism of this reaction, however, is not yet fully
established. Since phenols and naphthols are very strong acids
in the excited state, it is proposed that the excitation of
o-hydroxybenzyl alcohols results in an excited state intramo-
lecular proton transfer (ESIPT) of a phenolic proton to an
oxygen atom in the benzylic position. The C-O bond heterolysis
might proceed in a concerted fashion with ESIPT. On the other
hand, there is some evidence that loss of water happens in the
ground state after proton transfer is complete.6 Our research
(1) (a) Wan, P.; Brousmiche, D. W.; Chen, C. Z.; Cole, J.; Lukeman, M.;
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, 1988; Vol. 2, Part 1, pp 455-536; (e)
Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
(f) Fischer, M.; Shi, Y.; Zhao, B.-p.; Snieckus, 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 therein.
(2) (a) Freccero, M. Mini-ReV. Org. Chem. 2004, 1, 403. (b) Lignins:
Occurrence, Formation, Structure and Reactions; Sarkanen, K. V.,
Ludving, C., Eds.; Wiley: New York, 1971; (c) Stowell, J. K.;
Widlanski, T. S.; Kutateladze, T. G.; Raines, R. T. J. Org. Chem.
1995, 60, 6930.
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Chem. 2005, 12, 2893–2931. (b) Freccero, M.; Di Valentin, C.; Sarzi-
Amade, M. J. Am. Chem. Soc. 2003, 125, 3544–3553. (c) Weng, X.;
Ren, L.; Weng, L.; Huang, J.; Zhu, S.; Zhou, X.; Weng, L. Angew.
Chem., Int. Ed. Engl. 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.
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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,
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M. A.; Tormos, R. J. Org. Chem. 2003, 68, 9647. (b) Chiang, Y.;
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9
11892 J. AM. CHEM. SOC. 2009, 131, 11892–11899
10.1021/ja9031924 CCC: $40.75  2009 American Chemical Society

o-Naphthoquinone Methides in Aqueous Solutions
A R T I C L E S
Scheme 1
Scheme 2
group uses photochemical reactions of o-hydroxybenzyl alcohol
analogues for the development of photolabile protecting groups.7
Since the parent o-hydroxybenzyl chromophore has little
absorbance above 250 nm, it is hardly suitable for practical
applications. The absorbance of 3-hydroxymethyl- (3a) and
1-hydroxymethyl-2-naphthols (4a, Scheme 2), on the other hand,
extends beyond 350 nm (Figure 1). Additionally, we expected
that higher excited state acidity of 2-naphthol8 will facilitate
ESIPT and enhance the efficiency of oQM formation. In this
report, we discuss the generation and reactivity of two isomeric
o-naphthoquinone methides (oNQM), 2,3-naphthoquinone-3-
methide (1) and 1,2-naphthoquinone-1-methide (2, Scheme 2).
Figure 1. UV-spectra of ca. 10-5 M aqueous solutions of 3a (dashed line)
and 4a (solid line).
Results and Discussion
Three sets of precursors were employed for the generation
of oNQMs 1 and 2: 3-hydroxy-2-naphthalenemethanol (3a) and
2-hydroxy-1-naphthalenemethanol (4a); 3-ethoxymethyl- (3b)
and 1-(ethoxymethyl)-2-naphthols (4b); (2-hydroxy-3-naphth-
yl)methyl- (3c) and [(2-hydroxy-1-naphthyl)methyl] trimethy-
lammonium iodides (4c, Scheme 2).9 Kinetics of the oNQM
reactions was studied in aqueous solutions using a nanosecond
kinetic spectrometer equipped with a pulsed Nd:YAG laser.10
The quantitative product analysis of photolysis mixtures were
conducted by HPLC using individual compounds as references.
Preparative photolyses were performed in aqueous acetonitrile
solutions.
Figure 2. Emission spectra at λex ) 305 nm of ca. 10-5 M aqueous solutions
of 3a (dashed line) and 4a (solid line).
Properties and Reactivity of oNQM Precursors. UV spectra
of 3-hydroxy-2-naphthalenemethanol (3a) and 2-hydroxy-1-
naphthalenemethanol (4a) are expectedly similar and resemble
the spectrum of 2-naphthol (Figure 1). In aqueous solution, UV
spectra of compounds 3a and 4a contain two major absorption
bands above 210 nm: at λmax ) 275 nm (3a, log ε ) 4.06), 277
nm (4a, log ε ) 4.06), and at λmax ) 324 nm (3a, log ε ) 3.70
and 4a, log ε ) 3.83). Both bands show pronounced vibrational
structure. Both diols 3a and 4a show strong fluorescence. Their
emission spectra in aqueous solutions are almost identical and
contain two major bands at 360 and 423 nm (Figure 2).
2-Hydroxy-1-naphthalemethanol (4a), however, shows some-
what higher fluorescence efficiency (ΦFl ) 0.30 ( 0.01) than
3a (ΦFl ) 0.230 ( 0.002).10 Upon 266 nm laser pulse excitation
the fluorescence intensity of these compounds rapidly decays
with the time constant of τFL ∼ 7 ns (3a) and 8 ns (4a). While
the spectra and fluorescent quantum yields of 3a and 4a are
similar to those of 2-naphthol (ΦFl ) 0.27),11 fluorescence
lifetimes are somewhat shorter than for 2-naphthol (τFL ∼ 11
ns).12 This observation apparently indicates that a new pathway
for the excited state decay is opened for 3a and 4a. Spectral
properties of oNQM precursors 3b,c and 4b,c are similar to
those of the parent diols.
The ground-state acidities of 3-hydroxy-2-naphthalenemetha-
nol (3a) pKa ) 9.01 and 2-hydroxy-1-naphthalene-methanol (4a)
pKa ) 8.93 were determined by spectrophotometric titration in
aqueous solution at 25 ( 0.1 °C (Figure 3).10 These values are
about 0.5 units lower than the pKa of 2-naphthol (9.5-9.6).13
The enhanced acidity of 3a and 4a can be apparently explained
(6) (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.
(11) (a) Birks, J. B. Photophysics of Aromatic Molecules; Wiley Inter-
science: New York, 1970; 703 p; (b) Datta, S.; Mukhopad, C.;
Bhattacharya, S.; Bose, S. K. Spectrochim. Acta, Part A 2006, 64,
116.
(7) (a) Kostikov, A.; Popik, V. V. Org. Lett. 2008, 10, 5277. (b) Kulikov,
A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73 (19), 7611.
(c) Kostikov, A.; Popik, V. V. J. Org. Chem. 2007, 72, 9190.
(8) Wan, P.; Shukla, D. Chem. ReV. 1993, 93, 571.
(9) Preparation of the precursors 3a-c and 4a-c is described in the
Supporting Information.
(12) (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–
2434. (b) Berlman, I. B. Handbook of Fluorescence Spectra of
Aromatic Molecules; Academic Press: New York, 1971; 473p.
(10) See Supporting Information for details.
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A R T I C L E S
Arumugam and Popik
Table 1. Yields of the Hydration Product (3a, 4a) and Ethyl Vinyl
Ether Adduct (5, 6)
QM
precursor
yield of hydration
product/% (conversion)a, b
yield of ethyl vinyl
ether adduct/% (conversion)a, c
e
-
3b
3c
4b
4c
95 ( 1 (11%)
76 ( 1 (56%)
95 ( 1 (11%)
76 ( 3 (68%)
95 ( 4 (13%)
76 ( 3 (53%)
96 ( 1 (11%)
70 ( 3 (61%)
96 ( 1 (91%)
89 ( 1 (99%)
95 ( 1 (91%)
87 ( 1 (99%)
b
c
a λirr ) 254 or 300 nm. Ca. 6 × 10-4 M in water. Ca. 3 × 10-4
M
solutions of the substrate. d Ca. 0.03 M ethyl vinyl ether. e In 50%
CH3CNaq.
.
acetonitrile in the presence of ethyl vinyl ether resulted in
the formation of adducts 5 and 6 in 87% isolated yields.10
The former products were also formed when 355 nm
monochromatic radiation15 was used for photolysis of 3a and
4b; conversion, however, was rather slow due to a week
substrate absorbance at this wavelength (Figure 1). HPLC
analysis shows near quantitative formation of vinyl ether
adducts in photolyses of alternative precursors 3b,c and 4b,c,
even at high conversions (Table 1). Interestingly, 2-ethoxy-
benzochromans 5 and 6 are photochemically stable and show
virtually no decomposition even after prolonged irradiation
at 254 or 300 nm. It is also important to note that adducts 5
and 6 are formed almost quantitatively in the photolyses of
ethyl ethers 3b and 4b even at low conversion (Table 1).
The quantitative formation of Diels-Alder adducts despite
the presence of more than a 1000-fold excess (33 M versus
0.03 M) of a nucleophilic solvent indicates that addition of
ethyl vinyl ether to oNQMs is at least 2 orders of magnitude
faster than a hydration reaction. Direct rate measurements
(Vide infra) enabled us to quantify this rate difference.
Formation and Reactivity of 2,3-Naphthoquinone-3-methide
(1) and 1,2-Naphthoquinone-1-methide (2). Substrate concentra-
tions in aqueous solutions for kinetic measurements were of
the order of 10-5 M, and the temperature of these solutions was
controlled at 25 ( 0.1 °C. Excitation of naphthols 3a and 4a
with 4 ns 266 nm pulses of a Nd:YAG laser under these
conditions results in the formation of short-lived transients (τ
) 12-13 µs) with λmax at 370 nm, which rapidly decay to yield
new intermediates with λmax at 330 nm and broad absorption
extending to 430 nm (Figure 4). The latter transients then decay
at somewhat slower rate (τ ) 4-8 ms).
Upon laser pulsed excitation, both naphthols 3a and 4a
produce a burst of bright fluorescence covering the region from
320 to 500 nm (Figure 2). This intense emission saturates the
detector and produces significant artifacts when measurements
are made within this spectral region. Hence, the formation and
decay of the both reactions were monitored at 310 nm, where
the fluorescence interference was negligible.
Since the rates of the rise and the decay of oNQM absorbance
were sufficiently different (Vide infra), these processes were
recorded in separate experiments using different time scales and
signal amplifications. The observed first-order rate constants
were obtained by fitting experimental data separately to single
exponential functions (Figure 5).10 Decay of the intermediate
generated in the photolysis of 3a is relatively slow in aqueous
solution (kobs ) 135 ( 7 s-1 at pH ) 7.0), but is strongly
Figure 3. Spectrophotometric titration of diol 3a. The inset shows spectra
of 3a and its anion (dashed line).
Scheme 3
by the formation of an anion-stabilizing intramolecular hydrogen
bond between negatively charged phenolate oxygen and a
benzylic hydroxy group.
The 254 or 300 nm irradiation of aqueous solutions of oNQM
precursors 3a and 4a did not produce detectable amounts of
new products, apparently because the formation of oNQM 1
and 2 is followed by the rapid and efficient rehydration to yield
starting materials (Vide infra). Photolysis of the aqueous
solutions of ethyl ethers 3b and 4b, on the other hand, results
in rapid consumption of the substrates and the formation of 3a
and 4a, respectively (Scheme 3). The quantum yield for the
photoelimination of ethanol from 3b and 4b at 254 nm was
determined using ferrioxalate actinometry:10 Φ3b ) 0.17 ( 0.02
and Φ4b ) 0.20 ( 0.01. Chemical yields of 3a and 4a are almost
quantitative at low conversions, but are somewhat reduced at
longer irradiation times, apparently due to secondary photo-
chemical processes (Table 1). No new photoproducts were
detected by HPLC or isolated by flash chromatography,
however, even after prolonged photolysis of 3a,b. This observa-
tion suggests that the secondary photoproducts are most likely
oNQM oligomers,14 which were trapped in the column.
Quinone methides are known to undergo very efficient
hetero Diels-Alder reactions with electron-rich alkenes.5 The
254 or 300 nm irradiation of naphthols 3a and 4a in aqueous
(13) (a) Ireland, J. F.; Wyatt, P. A. H. AdV. Phys. Org. Chem. 1976, 12,
131. (b) Park, S.; Kim, H.; Kim, K.; Lee, J.; Lho, D. Phys. Chem.
Chem. Phys. 1999, 1, 1893.
(14) (a) Itoh, T. Prog. Polym. Sci. 2001, 26, 1019. (b) Dolenc, J.; Sket, B.;
Strlic, M. Tetrahedron Lett. 2002, 43, 5669.
(15) Frequency tripled output of Nd:YAG laser.
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o-Naphthoquinone Methides in Aqueous Solutions
A R T I C L E S
Figure 4. Transient spectra of obtained 1 µs (dashed line) and 1 ms (solid line) after the laser pulse in photolysis of ca. 0.01 mM aqueous solutions of 3a
(A) and 4a (B) at pH ) 7.0.
Figure 5. Formation and decay of 2,3-naphtho-quinone-3-methide (1) in
Figure 6. Quenching of oNQM 1 by ethyl vinyl ether (hexagons); sodium
the photolysis of ca. 0.01 mM aqueous solution of 3a at pH ) 7.0.
azide (triangles); and thioethanolamine hydrochloride (circles) in aqueous
solutions at pH ) 7.0.
affected by the addition of reactive nucleophiles or electron-
rich dienophiles (Figure 6, Table 2).10 Thus, the azide ion
Table 2. Second-Order Rates of oNQMs 1 and 2 Reactions with
Various Trapping Agents
(kN3 ) 2.00 × 104 M-1 s-1) and thiolethanolamine hydrochloride
(kSH ) 2.24 × 105 M-1 s-1) efficiently trap the intermediate.
NaN3
k/M-1 s-1
HSCH2CH2NH3 ·HCl
k/M-1 s-1
CH2dCH-O-C2H5
k/M-1 s-1
QM precursor
The rate of decay is also linearly proportional to the concentra-
tion of ethyl vinyl ether (kEVE ) 4.07 × 104 M-1 s-1). Since
the product studies indicated that the photolysis of 2-naphthol
derivatives 3a-c in the presence of ethyl vinyl ether ultimately
produces 2-ethoxybenzochroman 5, this observation enables us
to identify the intermediate as 2,3-naphthoquinone-3-methide
(1, Scheme 3). The second order rate constants of oNQM 1
reactions with various trapping agents are summarized in Table
2. It is interesting to note that UV absorbance of oNQMs is
blue-sifted from that of the parent oQM (Scheme 1).1a,b,5b This
observation is consisitent with previous reports on a binaphthol
analogue.3e,f
3a
3c
4a
4c
(2.00 ( 0.11) × 104 (2.24 ( 0.06) × 105 (4.07 ( 0.19) × 104
(2.04 ( 0.46) × 104 (2.22 ( 0.05) × 105 (4.26 ( 0.13) × 104
(3.00 ( 0.25) × 104 (3.34 ( 0.28) × 105 (6.05 ( 0.34) × 104
(2.75 ( 0.05) × 104 (3.30 ( 0.86) × 105 (6.01 ( 0.42) × 104
mentioned earlier, preparative photolysis of 3c in the presence
of ethyl vinyl ether allows for trapping of oNQM 1 as
Diels-Alder adduct 5 in 89% preparative yield (Table 1). Laser
flash excitation of 3c at 266 nm generates a reactive intermedi-
ate, whose spectral properties and reactivity are identical to
oNQM 1 (Table 2). It is interesting to note that the formation
of 1 in the photolysis of ammonium precursor 3c is complete
within the duration of a laser pulse (ca. 6 ns) and no kinetic
precursors to oNQM 1 were observed in this case.
o-Hydroxybenzyl trimethylammonium salts are also known
to generate oQMs upon irradiation.16 To explore the alternative
source of oNQM, we have studied the photochemistry of (2-
hydroxy-3-naphthyl)methyltrimethylammonium iodide (3c). As
In aqueous solutions, in the absence of nucleophiles or
dienophiles, naphthoquinone methide 1 undergoes hydration to
(16) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem. 2001,
66, 41.
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A R T I C L E S
Arumugam and Popik
yield 3-hydroxy-2-naphthalenemethanol (3a), as evident from
the results of preparative photolyses of 3b and 3c (Table 1,
Scheme 3).
Flash photolysis of 2-hydroxy-1-naphthalenemethanol (4a)
enabled us to observe the formation and decay of the isomeric
1,2-naphthoquinone-1-methide (2, Scheme 3). The reactivity of
oNQM 2 is very similar to that of 1, although the rate of
hydration in aqueous solution was somewhat higher (kobs ) 224
( 6 s-1, pH ) 7.0). oNQM 2 is also about 25-30% more
reactive toward nucleophiles (NaN3 and thioethanolamine HCl),
as well as ethyl vinyl ether (Table 2). oNQM 2 was also
generated from [(2-hydroxy-1-naphthyl)methyl] trimethylam-
monium iodides (4c, Table 2). The rate of reaction of oNQMs
1 and 2 with thiols (Table 2) is similar to that of the parent
o-quinone methide with 2-mercaptoethanol (kSH ) 1.9 × 105
M-1 s-1).16
Kinetics of Hydration of o-Naphthoquinone Methides in
Perchloric acid, Base, and Buffer Solutions. Rates of the
hydration of oNQM 1 and 2 were determined in dilute aqueous
solutions of perchloric acid and sodium hydroxide, as well as
in biphosphate ion and bicarbonate ion buffers. The ionic
strength of these solutions was kept constant at 0.1 M by adding
sodium perchlorate as required, except for the measurements
conducted at pH < 1. Kinetic data obtained in perchloric acid
solutions and in buffers obeyed the first-order rate law well,
and observed pseudo-first-order rate constants were determined
by least-squares fitting to a single exponential function. In
aqueous sodium hydroxide solutions, reactions of oNQMs 1 and
2 generated from precursors 3a and 4a showed complex kinetic
behavior. The rate of the reaction did not fit the exponential
law well and was dependent on the substrate concentration. We
believe that this phenomenon is most likely due to the reaction
of oNQMs with the deprotonated form of the substrate (3a or
4a). Similar complex behavior was previously observed in
photolyses of o-hydroxybenzyl alcohol.17 Photolyses of (2-
hydroxy-3-naphthyl)methyl- (3c) and [(2-hydroxy-1-naphthyl)-
methyl] trimethylammonium iodides (4c) in basic solutions, on
the other hand, produce clean pseudo-first-order kinetics.
Therefore, hydration of oNQMs 1 and 2 in sodium hydroxide
solutions was studied using precursors 3c and 4c. Rate
measurements in buffered solutions were performed in series
of solutions of varying buffer concentration but constant
buffer ratio. The observed rates were then extrapolated to a
zero buffer concentration. While no appreciable buffer
catalysis was observed, the zero-concentration intercepts were
well-determined. The buffer-independent rate constants,
together with observed rate constants determined in perchloric
acid and sodium hydroxide solutions, are shown as the rate
profile in Figure 7.
Figure 7. Rate profile for the hydration of oNQM 1 (empty circles) and 2
(filed squares) in aqueous solution at 25 °C. Inset illustrates the dependence
of the signal intensity of oNQM 1 on perchloric acid concentration.
benzyl alcohol pKa* ∼ 2.55c versus phenol pKa* ∼ 3.6.18 The
nature of this effect is probably the same as in the ground state
(Vide supra): stabilization of an anion by intramolecular
hydrogen bond between negatively charged phenolate oxygen
and a benzylic hydroxy group.
The rate of hydration of oNQMs 1 and 2 is independent of
the acidity of aqueous solutions in the range from pH 1 to 8
resulting in a broad horizontal region in the rate profile (Figure
7). The observed rate constants on this plateau are k ) 145
H2O
( 12 s-1 for oNQM 1 and k ) 229 ( 14 s-1 for oNQM 2.
H2O
These values are very similar to uncatalyzed hydration of the
parent oQM (k
) 260 s-1).19 Also, these values are in
H2O
excellent agreement with those obtained from flash photolysis
of 3a and 4a at pH 7.7b The rate of hydration of the parent
oQM, however, showed pronounced specific acid catalysis (kH+
) 8.4 × 105 M-1 s-1),5b,18 which was assigned to the rapid
pre-equilibrium protonation of the oQM, which produces a more
reactive o-hydroxybenzyl cation. The acid catalysis of the
hydration of oNQM 1 is much weaker (kH+ ) 299 ( 11 M-1
s-1) and becomes prominent only at pH < 1. We were not able
to study H+-catalyzed hydration of an isomeric oNQM 2 because
its precursors 4a-c are unstable in acidic solutions at [H+] >
0.1 M. Weaker acid catalysis of oNQMs 1 and 2 hydration can
apparently be explained by the lower basicity of naphthoquinone
methides versus oQMs (compare, for example, 2-naphthol, pKa
) 9.5-9.613 and phenol pKa ) 10.020). In addition, the reactivity
of protonated oNQMs is potentially lower due to an increased
delocalization of the positive charge.
The hydration of oNQMs 1 and 2 is strongly catalyzed by
the hydroxide-ion, as illustrated by the upward slope of the rate
profile at pH > 10. The rate constant for hydroxide-ion catalyzed
hydration is kOH ) (3.30 ( 0.03) × 104 M-1 s-1 for oNQM 1
and kOH ) (3.74 ( 0.04) × 104 M-1 s-1 for NQM 2. The
reactivities of oNQMs 1 and 2 toward nucleophilic attack by
the hydroxide-ion are very similar to the parent o-quinoneme-
thide (kOH ) 3.0 × 104 M-1 s-1). The rate profile of Figure 7
is readily understood in terms of this reaction scheme (Sch-
eme 4).
It is interesting to note that quantum yield of oNQM
generation rapidly decreases at [H+] > 0.1 M and no oNQM
signal is observed at [HClO4] > 1 M (see inset in Figure 7).
Since photochemical dehydration of o-hydroxybenzyl alcohol
and its analogues, such as 3a, proceeds via deprotonation of
the phenolic hydroxyl in the excited state, this phenomenon
enables us to evaluate the excited state acidity of 3-hydroxy-
2-naphthalenemethanol (3a). The inflection point on the sigmoid
titration curve (inset in Figure 7) corresponds to pKa* ) 0.77
( 0.04. This makes 3a* 100 times more acidic than 2-naphthol
in the exited state (pKa∼ 2.8).13 Similar acidifying effect of the
o-hydroxymethyl substituent was also reported for o-hydroxy-
(18) Gao, J.; Li, N.; Freindorf, M. J. Am. Chem. Soc. 1996, 118, 4912.
(19) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2001, 123, 8089.
(20) Bordwell pKa tables: http://www.chem.wisc.edu/areas/reich/pkatable/
index.htm.
(17) Wan, P.; Hennig, D. J. Chem. Soc., Chem. Commun. 1987, 939.
9
11896 J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009

o-Naphthoquinone Methides in Aqueous Solutions
A R T I C L E S
within the uncertainty limits (kH O ) 132 ( 10 M-1 s-1).
Scheme 4
2
[(2-Hydroxy-1-naphthyl)methyl] trimethyl ammonium iodide
(4c) is unstable in aqueous solutions at pH < 4; therefore,
the rate measurements were performed in a biphosphate
buffer at pH ) 7.0 to give kH O ) 201 ( 6 M-1 s-1. This
2
value is similar to the rate of hydration of 2 obtained in laser
flash photolysis of diol 4a.
Nature of the oNQM Precursor. While the formation of
oNQMs 1 and 2 in the flash photolysis of ammonium
precursors 3c and 4c happens within the duration of a laser
pulse, irradiation of 3-hydroxy-2-naphthalenemethanol (3a)
and 2-hydroxy-1-naphthalenemethanol (4a), as well as their
ethoxy derivatives 3b and 4b, allows for the detection of a
kinetic precursor to oNQMs. Thus, the formation of oNQM
1 in aqueous solution proceeds with the observed rate of kobs
) (8.03 ( 0.04) × 104 s-1 (Figure 5) and kobs ) (8.10 (
0.07) × 104 s-1 for oNQM 2. In agreement with previously
reported data,5b we did not observe kinetic precursors to the
parent o-quinone methide in the laser flash photolysis of
o-hydroxybenzyl alcohol. The rate of oNQMs formation is
independent of pH of the solution and is not affected by the
presence of the azide ion, thiolethanolamine hydrochloride,
or ethyl vinyl ether. The fluorescence lifetime of 3a (τ ∼ 7
ns, Vide supra) is much shorter than the rise time of oNQM
1, indicating that the latter species is not formed directly
from the singlet excited state of 3a. The spectrum of 3a and
4a fluorescence is essentially identical to that of 2-naphtol,
suggesting that no significant structural changes occur at the
singlet excited state surface. Since saturation of the solution
with oxygen or addition of increased 1,3-cyclohexadiene do
not quench the first transient, we can conclude that triple
excited state of 3a is not involved in the formation of oNQM
1. The zwitterionic structure 7 can be also excluded from
consideration because proton transfer between electronegative
atoms in aqueous solution proceeds at least at the diffusion-
controlled rate limit. In addition, the rate of decay of 7 should
be dependent on the acidity of solution, which is not
observed.
The base-catalyzed portion of the rate profiles apparently
corresponds to the rate-limiting attack of the hydroxide ion
on the methide carbon of oNQMs 1 and 2. The observed
weak acid catalysis at [H+] > 0.1 M should be assigned, as
in case of the parent oQM,5b,18 to the rapid pre-equilibrium
protonation of the oNQM, which produces the more reactive
cation 1+ (Scheme 4). The uncatalyzed portion at pH < 9
has two possible interpretations, the first of which is
reversible protonation of the oNQM by water, followed by
cation capture by the hydroxide ion so formed. This mech-
anism can be ruled out on the basis of the very weak specific
acid catalysis of hydration. The more probable mechanism
of the uncatalyzed reaction is simple nucleophilic attack of
water on the oNQM methylene group, with or without
simultaneous proton transfer to avoid a zwitterionic inter-
mediate (7, Scheme 4). Rates of hydration of oNQMs 1 and
2 were also measured in D2O solutions of deuterated
hydrochloric acid in the range of concentrations from 0.001
to 0.1 M. As in the case of H2O, no acid catalysis was
observed in this range of acidities, but the reaction was
appreciably slower, producing solvent kinetic isotope effect
in the normal direction (kH O/kD O ) 1.85 ( 0.14 for 1 and
2
2
kH O/kD O ) 1.42 ( 0.07 for 2). The nature of this isotope
2
effect s2tems from the fact that positively charged O-H bonds,
such as those in the intermediate 7 (Scheme 4), are looser
than uncharged O-H bonds, such as those in a water
molecule.21 Conversion of H2O into ROH2 leads to a
+
loosening of the hydrogenic environment of the species
involved, and that produces an isotope effect in normal
direction.
The rate of hydration of oNQM 1 generated from am-
monium precursor 3c in neutral conditions and in 0.1-0.001
M perchloric acid matches the results obtained using 3a
Excited state proton transfer from the phenolic oxygen to the
aromatic carbon in the singlet excited state is well-documented
Scheme 5
9
J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009 11897

A R T I C L E S
Arumugam and Popik
for phenols and naphthols.22 Such carbon protonation leading
to keto-intermediate 8 or its isomers should result in incorpora-
tion of deuterium in hydration products when photolysis is
conducted in deuterated 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 enables us to rule out participation of 8 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 In addition, thermolysis of thio-analogues of
diols 3a and 4a produce the corresponding isomeric
naphthothietes.23a We believe that in our case, oxetanes 9
and 10 are the likely precursors of o-naphthoquinone me-
thides 1 and 2 (Scheme 5).
Additional support for this mechanism comes from the fact
that excitation of trimethylammonium derivatives 3c and 4c
directly produces corresponding oNQMs, bypassing inter-
mediates 9 and 10. Dissociation of the highly acidic excited
states of 2-naphthol derivatives 3 and 4 produce anions 3-
and 4- (Scheme 5). When “X” is a good leaving group, such
as trimethylamine, these anions might form oNQMs directly.
In the case of poor leaving groups, such as hydroxyl or
alkoxyl, an intramolecular SN2 reaction produces oxetenes 9
or 10. Ring-opening of the latter to give oNQMs 1 and 2 is
an electrocyclic reaction and, therefore, is not sensitive to
acid/base catalysis or the presence of reactive nucleo-
philes.
Theoretical Analysis. To gain a better understanding of the
difference in the kinetics of the formation of oNQMs and the
parent o-quinonemethide 12 (Scheme 6), we conducted com-
putational comparison of these two reactions. The ring-opening
of naphthoxete 9 is much slower than a decay of an excited
state of 3a (Vide supra) and is, apparently, a thermal reaction.
We have analyzed the reactivity and relative stability of oxetenes
9 and 11 at the B3LYP/6-311++G(d,p)//B3LYP/6-31++G(d,p)
and MP2/6-31++G(d,p)//FC-MP2/6-31++G(d,p) levels of
theory. The geometries of transition states 9q and 11q (Scheme
6) were also optimized by open-shell UB3LYP/6-31++G(d,p)
calculations. The latter, however, converged to the same
structures and energies as closed-shell calculations. The opti-
mized geometries of structures 1, 9, 9q, 11, 11q, 12, as well as
the details of theoretical procedures, are provided in the
Supporting Information file.10 The relative electronic energies
of isomeric oxetenes and o-quinonemethides, ring-opening
transition states (9q and 11q), and C-O distances are shown in
Table 3.
Scheme 6
Table 3. Relative Electronic Energies and C-O Distances for
Oxetanes 9 and 11, o-Quinonemethides 1 and 12, and Transition
States 9q and 11q
∆E (kcal/mol)a
B3LYP/6-311++G(d,p)
MP2/6-31++G(d,p)
C-O distance (Å)
9
0.0
31.2
0.2
0.0
26.6
-13.2
0.0
35.0
4.8
0.0
31.3
-7.4
1.49
2.10
2.81
1.49
2.06
2.82
9q
1
11
11q
12
a ZPVE, corrected energy; electronic energy of 9 was used as a
reference for oNQM system, and 11 - for oQM system.
Calculation results shown in Table 3 illustrate the striking
difference between benzene and naphthalene-derived systems.
The parent oQM (12) is substantially more stable than its
potential precursor benzoxete (11). The electronic energy of
oNQM 1, on the other hand, is close to (DFT) or even higher
than that of naphthoxete (9). The energies of transition states
9q and 11q are rather high in the gas phase but can be
significantly reduced in polar solvents capable of hydrogen
bonding. However, both DFT and MP2 methods predict that
the barrier for the ring-opening of 11 to yield 12 is about 4
kcal/mol lower than for opening of 9 to 1. A higher relative
energy and lower activation barrier for the electrocyclic ring-
opening of 11 suggests that these species are thermally
unstable and decay within a duration of laser pulse if formed
in the photolysis of o-hydroxybenzyl alcohol.
Conclusions
The isomeric 2,3-naphthoquinone-3-methide (1) and 1,2-
naphthoquinone-1-methide (2) are predictably very reactive
species and undergo efficient hydration in aqueous solutions to
form 3-hydroxy-2-naphthalenemethanol (3a) and 2-hydroxy-1-
naphthalenemethanol (4a), respectively. These o-naphthoquinone
methides react even faster with good nucleophiles, such as thiols
and the azide ion. What is surprising is that the reactivity of
regioisomers 1 and 2 is quite similar, despite vastly different
electronic structures. In fact, the rate of the addition of various
nucleophiles to o-naphthoquinone methides is close to that of
the parent o-quinone methide. The only significant difference
from the parent system is the much weaker acid catalysis of
the hydration reaction, apparently due to the lower basicity
of oNQMs versus oQM. The hetero-Diels-Alder reaction of
oNQM 1 and 2 with ethyl vinyl ether is very facile and produces
high yield of 2-ethoxybenzochromans, even in aqueous solution.
These adducts are photochemically stable and might be em-
ployed for photochemically induced cross-linking or ligation.
From a practical point of view, the generation of reactive
o-quinone methides by photolysis of 2-hydroxynaphthalene
methanols is more convenient than from o-hydroxybenzylalco-
hols because 350 nm light can be employed.
(21) 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.
(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.
(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.
(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.
9
11898 J. AM. CHEM. SOC. VOL. 131, NO. 33, 2009

o-Naphthoquinone Methides in Aqueous Solutions
A R T I C L E S
Another interesting feature of the photochemistry of 3a and
4a is the observation of a kinetic precursor to oNQMs. On the
basis of the analysis of the reactivity of these species and the
results of DFT calculations, we have assigned the naphthoxete
structure to these transients.
Supporting Information Available: Experimental details;
synthetic procedures for the preparation of compounds 3a-c
and 4a-c; details of kinetic measurements; Cartesian coordi-
nates of DFT-optimized structures. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Authors thank the National Science Founda-
tion (CHE-0449478), and donors of the ACS Petroleum Research
Fund (434444-AC4) for the support of this project.
JA9031924
9
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