A R T I C L E S
Tsuji et al.
encounter between the free ions 1+ and PhO- and by the spon-
taneous solvolytic cleavage of 1-OPh.
Scheme 2
Experimental Section
Materials. Unless noted otherwise, inorganic salts and organic
chemicals were reagent grade from commercial sources and were used
without further purification. The water used for kinetic studies and
HPLC analyses was distilled and then passed through a Milli-Q water
purification system. Deuterium oxide (99.9+% D) was from Cambridge
Isotope Laboratories and deuterium chloride (37wt %, 99.5% D) and
CF3CH2OD (99.5% D) were from Aldrich.
Syntheses. The following compounds were prepared by published
procedures: 1-(4-methoxyphenyl)ethanol (1-OH), 1-(4-methoxyphen-
yl)ethyl 3,5-dinitrobenzoate (1-(3,5-dinitrobenzoate)) and 1-(4-meth-
oxyphenyl)ethyl 4-nitrobenzoate (1-(4-nitrobenzoate)).12 The proce-
dures for the synthesis of the following compounds are given in the
Supporting Information: 1-OPh, 1-(2-C6H4OH), and 1-(4-C6H4OH).
Preparation of Solutions. Aqueous solutions of 1.0 M sodium azide
and sodium acetate were adjusted to pH ≈ 7 with concentrated HClO4
before they were used to prepare mixed trifluoroethanol/water solvents.
Solutions of 48/2/50 (v/v/v) trifluoroethanol/phenol/water that contained
sodium acetate and/or sodium azide at I ) 0.50 were prepared by mixing
an aqueous solution of the salt (5-20 mM, I ) 1.0 M, NaClO4 and pH
7) with 96/4 (v/v) trifluoroethanol/phenol. The solutions of 96/4 (v/v)
trifluoroethanol/phenol was prepared by mixing TFE at room temper-
ature with liquid phenol at its melting point of 40 °C. Alkaline solu-
tions of azide ion in 48/2/50 (v/v/v) trifluoroethanol/phenol/water
were prepared by first mixing 1.0 M NaOH with an equal volume of
96/4 (v/v) trifluoroethanol/phenol and then adding to the resulting
solution a measured volume of 48/2/50 (v/v/v) trifluoroethanol/phenol/
water that contained 5 mM NaN3 at I ) 0.50 (NaClO4). Buffered
solutions of 50/50 (v/v) trifluoroethanol/water (I ) 0.50, NaClO4) were
prepared by mixing aqueous solutions (I ) 1.0, NaClO4) which con-
tain 40 mM of the specified buffer with an equal volume of
trifluoroethanol.
Stock solutions of 50/50 (v/v) CF3CH2OL/L2O (L ) H, D) that
contain LCl at I ) 0.50 (NaClO4) were prepared by mixing
CF3CH2OL with an equal volume of L2O that contained LCl (I ) 1.0
NaClO4). These stock solutions were diluted by mixing with 50/50
(v/v) CF3CH2OL/L2O (I ) 0.5 NaClO4).
Product Studies. All product studies were at 25 °C. Reactions of
1-(3,5-dinitrobenzoate) (2 mM) in 48/2/50 (v/v/v) trifluoroethanol/
phenol/water were initiated by making a 100-fold dilution of the
substrate, dissolved in acetonitrile, into the mixed solvent which
contained 5 mM NaN3 and acetate ion (2.5-10 mM). The product yields
were determined several times over a 3 h reaction period.
Reactions of 1-(3,5-dinitrobenzoate) (2 mM) in 48/2/50 (v/v/v)
trifluoroethanol/phenol/water (I ) 0.5, NaClO4) which contained azide
ion and increasing concentrations of the conjugate bases of solvent
were initiated by making a 100-fold dilution of the substrate, dissolved
in acetonitrile, into the mixed solvent. After 60 min. [ca. 2 halftimes
for reaction of 1-(3,5-dinitrobenzoate)], sodium phenoxide was
neutralized by addition of 1 equiv acetic acid (2 M solution) and the
product yields were determined by HPLC analysis. The solution
contained 10 µM fluorene, which served as an internal standard to
correct for small variations in the volume of the sample analyzed by
HPLC.
The perchloric acid-catalyzed reaction of 1-OH (0.25 mM) in
50/50 (v/v) trifluoroethanol/water that contained 0.5 M HClO4 and
18 mM phenol was initiated by making a 100-fold dilution of the
substrate, dissolved in acetonitrile, into the mixed solvent. The acid
was neutralized by addition of one equivalent of sodium acetate (2 M
solution) at measured reaction times and the product yields were
determined by HPLC analysis. The reaction of 1-OPh in 48/2/50
(v/v/v) trifluoroethanol/phenol/water that contained 0.012 M HClO4 (I
) 0.5, NaClO4) was initiated by making a 100-fold dilution of the
dissect the underlying cause for the high basicity of carbon
compared with oxygen toward these reactive carbon electro-
philes.
The 4-methoxybenzyl and 1-(4-methoxyphenyl)ethyl car-
bocations have been generated as intermediates of solvoly-
sis12,13 and photochemical reactions,14,15 and have been shown
to be sufficiently stabilized by electron-donation from the
4-methoxybenzyl ring to diffuse through aqueous solution.
Studies to characterize the rate and equilibrium constants for
formation and reaction of these carbocations in aqueous sol-
vents have provided a large body of information on the mech-
anism for solvolysis and carbocation-nucleophile combination
reactions.12,13,16-18
1-(4-Methoxyphenyl)ethyl phenyl ether (1-OPh) undergoes
acid-catalyzed cleavage to form phenol and the 1-(4-methoxy-
phenyl)ethyl carbocation (1+); and, 1+ generated by cleavage
of 1-(4-methoxyphenyl)ethyl substituted benzoates is trapped
by phenol to form 1-OPh in a reaction that is catalyzed by
Brønsted bases.12,17 We report here the results of a comprehen-
sive study of the spontaneous and acid-catalyzed cleavage of
1-OPh; and, of carbon and oxygen alklyation of phenol and
phenoxide ion by 1+ (Scheme 2). We also report the high-level
ab initio calculation of the equilibrium constant for isomerization
of 1-OPh to 1-(2-C6H4OH) in water. This could not be obtained
by experiment, but is needed for a complete description of the
rate and equilibrium constants for C- and O-alklyation of phenol
by 1+.
These data provide a thorough description of this important
organic reaction, which includes the following: (1) a second
relatively rare example of an organic carbon nucleophile, phe-
noxide ion, with a reactivity toward carbocations that is similar
to that of the strong inorganic nucleophile azide ion;19,20 (2) a
description of the relative thermodynamic driving forces and
Marcus intrinsic barriers for ambident alkylation of phenol by
the carbon electrophile 1+ that is essential to an understanding
of the ambident reactivity of this nucleophile; and (3) a unique
comparison of the collapse of ion pairs generated by diffusional
(12) Richard, J. P.; Rothenberg, M. E.; Jencks, W. P. J. Am. Chem. Soc. 1984,
106, 1361-1372.
(13) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1990, 112, 9507-9512.
(14) McClelland, R. A. Tetrahedron 1996, 52, 6823-6858.
(15) McClelland, R. A.; Cozens, F. L.; Steenken, S.; Amyes, T. L.; Richard, J.
P. J. Chem. Soc., Perkin Trans. 2 1993, 1717-1722.
(16) Amyes, T. L.; Richard, J. P. J. Chem. Soc., Chem. Commun. 1991, 200-
202.
(17) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1396-1401.
(18) Toteva, M. M.; Richard, J. P. J. Am. Chem. Soc. 2002, 124, 9798-9805.
(19) Richard, J. P.; Lin, S.-S.; Williams, K. B. J. Org. Chem. 1996, 61, 9033-
9034.
(20) Williams, K. B.; Richard, J. P. J. Phys. Org. Chem. 1998, 11, 701-706.
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15456 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003