Kinetic and Thermodynamic Barriers to Carbon and Oxygen Alkylation of Phenol and Phenoxide Ion by the 1-(4-Methoxyphenyl)ethyl Carbocation

Article abstract of DOI:10.1021/ja037328n

Rate constant ratios for addition of the three nucleophilic sites of phenol to the 1-(4-methoxyphenyl)ethyl carbocation (1⁺) in 50/50 (v/v) trifluoroethanol/water were determined from the relative yields of the three phenol adducts, and absolute rate constants were determined from product rate constant ratios for addition of phenol and azide ion to 1⁺ using k_az = 5 × 10⁹ M^-1 s^-1 for the diffusion-limited reaction of azide ion. A selectivity of 230:20:1 was determined for alkylation of phenol at oxygen, C-4 and C-2 to form 1-OPh and biphenyls 1-(4-C₆H₄OH) and 1-(2-C₆H ₄OH), respectively, and of 2:2:1 for alkylation of the corresponding nucleophilic sites of phenoxide ion in diffusion-limited reactions. The Mayr nucleophilicity parameter for C-4 of phenol is N = 2.0. Encounter-limited addition of phenoxide ion to 1⁺ to form 1-OPh is faster than encounter-limited addition of oxygen anions that are either more or less basic than phenoxide ion. Only the products of solvolysis are observed from acid-catalyzed cleavage of 1-OPh in 50/50 (v/v) trifluoroethanol/water, but a 50% yield of biphenyls 1-(4-C₆H₄OH) and 1-(2-C ₆H₄OH) are observed from spontaneous cleavage of 1-OPh, where the leaving group is phenoxide ion, because of the very low kinetic barriers to collapse of the ion pair intermediate 1^+.PhO ^-. The 230-fold larger rate constant for O-compared to C-2-alkylation of phenol is due primarily to the larger thermodynamic driving force for oxygen addition. There are similar Marcus intrinsic barriers for these two reactions.

Full text of DOI:10.1021/ja037328n

Published on Web 11/20/2003
Kinetic and Thermodynamic Barriers to Carbon and Oxygen
Alkylation of Phenol and Phenoxide Ion by the
1-(4-Methoxyphenyl)ethyl Carbocation
Yutaka Tsuji,† Maria M. Toteva,‡ Heather A. Garth,§ and John P. Richard*,‡
Contribution from the Department of Biochemistry and Applied Chemistry, Kurume National
College of Technology, Komorinomachi, Kurume 830-8555, Japan, Department of Chemistry,
UniVersity of Minnesota, Minneapolis, Minnesota 55455, and Department of Chemistry,
UniVersity at Buffalo, SUNY, Buffalo, New York 14260-3000
Received July 16, 2003
Abstract: Rate constant ratios for addition of the three nucleophilic sites of phenol to the 1-(4-meth-
oxyphenyl)ethyl carbocation (1+) in 50/50 (v/v) trifluoroethanol/water were determined from the relative
yields of the three phenol adducts, and absolute rate constants were determined from product rate constant
ratios for addition of phenol and azide ion to 1+ using kaz ) 5 × 109 M-1 s-1 for the diffusion-limited reaction
of azide ion. A selectivity of 230:20:1 was determined for alkylation of phenol at oxygen, C-4 and C-2 to
form 1-OPh and biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH), respectively, and of 2:2:1 for alkylation of the
corresponding nucleophilic sites of phenoxide ion in diffusion-limited reactions. The Mayr nucleophilicity
parameter for C-4 of phenol is N ) 2.0. Encounter-limited addition of phenoxide ion to 1+ to form 1-OPh
is faster than encounter-limited addition of oxygen anions that are either more or less basic than phenoxide
ion. Only the products of solvolysis are observed from acid-catalyzed cleavage of 1-OPh in 50/50 (v/v)
trifluoroethanol/water, but a 50% yield of biphenyls 1-(4-C6H4OH) and 1-(2-C6H4OH) are observed from
spontaneous cleavage of 1-OPh, where the leaving group is phenoxide ion, because of the very low kinetic
barriers to collapse of the ion pair intermediate 1+•PhO-. The 230-fold larger rate constant for O-compared
to C-2-alkylation of phenol is due primarily to the larger thermodynamic driving force for oxygen addition.
There are similar Marcus intrinsic barriers for these two reactions.
Scheme 1
Introduction
The reactivities of phenol and phenoxide ion are strongly
affected by the delocalization of an electron pair from oxygen
onto the aromatic ring (Scheme 1), which causes a decrease in
the basicity of the phenol oxygen and an increase in the basicity
of the o- and p-carbons. This change in the relative basicity of
carbon and oxygen is not large enough to cause a change in
the preferred site for addition of the proton, a “hard”1,2 elec-
trophile, to phenoxide ion. However, alkyl and benzyl halides3-7
and carbocations,8-11 which are “softer” carbon electrophiles,
react at comparable rates to alkylate both the “hard” oxygen
and the “softer” ortho and para ring carbons of phenoxide ion.
Only qualitative conclusions about the underlying cause for
the large carbon nucleophilicity of phenol toward carbon electro-
philes have been drawn in earlier work. Several studies on
ambident carbon and oxygen alkylation of phenoxide ion have
focused on characterizing the solvent and salt effects on the
relative barriers to bimolecular nucleophilic substitution reac-
tions of these nucleophilic sites with benzyl and allyl halides.4-7
A thorough modern study has probed the importance of antihy-
drophobic cosolvent effects in determining the relative barriers
to O- versus C-alkylation for bimolecular substitution of phenox-
ide at the water-soluble electrophile p-carboxybenzyl chloride.3
There have been few studies of ambident nucleophilic addition
of phenol and phenoxide ion to carbocations,8-11 and none to
† Department of Biochemistry and Applied Chemistry, Kurume National
College of Technology.
‡ Department of Chemistry, University at Buffalo, SUNY.
§ Department of Chemistry, University of Minnesota.
(1) Pearson, R. G. J. Am. Chem. Soc. 1986, 108, 6109-6114.
(2) Pearson, R. G. Chemical Hardness; John Wiley & Son: New York, 1997.
(3) Breslow, R.; Groves, K.; Mayer, M. U. J. Am. Chem. Soc. 2002, 124, 3622-
3635.
(4) Gompper, R. Angew. Chem., Int. Ed. Engl. 1964, 3, 560-570.
(5) Kornblum, N.; Berrigan, P.; Noble, W. J. L. J. Am. Chem. Soc. 1960, 82,
1257-1258.
(6) Kornblum, N.; Berrigan, P. J.; LeNoble, W. J. J. Am. Chem. Soc. 1963,
85, 1141-1147.
(7) Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D. C. J. Am.
Chem. Soc. 1955, 77, 6269-6280.
(8) Hart, H.; Eleuterio, H. J. Am. Chem. Soc. 1954, 76, 519-522.
(9) Hart, H.; Eleuterio, H. J. Am. Chem. Soc. 1954, 76, 516-519.
(10) Okamoto, K.; Kinoshita, T.; Oshida, T.; Yamamoto, T.; Ito, Y.; Dohi, M.
J. Chem. Soc., Perkin Trans. 2 1976, 1617-1627.
(11) Okamoto, K.; Kinoshita, T.; Takemura, Y.; Yoneda, H. J. Chem. Soc.,
Perkin Trans. 2 1975, 1426-1433.
9
10.1021/ja037328n CCC: $25.00 © 2003 American Chemical Society
J. AM. CHEM. SOC. 2003, 125, 15455-15465
15455

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.
9
15456 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Barriers to C and O Alkylation of Phenol
A R T I C L E S
substrate in acetonitrile into the mixed solvent to give a final substrate
concentration of 2 mM.
and a value of 7.6 for the ratio of the peak areas for 1-OH and
1-OCH2CF3 determined for reaction in 50/50 (v/v) trifluoroethanol/
water at neutral pH.12 (e) (A1-N3) is the area of the peak for 1-N3. (f)
kaz/kTFE- ) 9 is the rate constant ratio for addition of azide and
trifluorethoxide ion to 1+.24
(2) The concentration of phenoxide ion ([PhO-]) was then calculated
as the difference between the concentration of NaOH used in preparing
the mixed solvent, and the value of [CF3CH2O-] determined from eq
3 and 4.
The reaction of 1-OPh (2 mM) in 48/2/50 (v/v/v) trifluoroethanol/
phenol/water which contained 0.012 M HClO4 (I ) 0.5, NaClO4) was
monitored by HPLC analysis until the ratio of the areas for 1-OCH2CF3
to 1-OPh remained constant with time. The equilibrium constant for
the conversion of 1-OCH2CF3 to 1-OPh was determined from eq 5,
where ([1-OPh]/[1-OCH2CF3])eq is the ratio of concentrations of the
phenyl and trifluoroethyl ethers observed at chemical equilibrium. 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 monitored for several days, until 1-OCH2CF3 had undergone
quantitative conversion to 1-(4-C6H4OH) and 1-(2-C6H4OH). Upper
limits for the ratio of the concentrations of the C-alkylated phenol
adducts and trifluoroethyl ether were calculated using the lowest level
of 1-OCH2CF3 detectable by HPLC analysis.
HPLC Analyses. The products of reactions of 1-Y were separated
by HPLC as described in previous work,13,21,22 and detected by their
UV absorbance at 274 nm which is λmax for 1-(4-methoxyphenyl)-
ethanol. The following compounds were identified by comparison with
known standards: 1-OH, 1-OCH2CF3, 1-OPh, 1-(4-C6H4OH), and
4-methoxystyrene. 1-(2-C6H4OH) was identified as the additional peak
observed upon HPLC analysis of a synthetic mixture of 1-(2-C6H4OH)
and 1-(4-C6H4OH).
Determination of Rate Constant Ratios and Equilibrium Con-
stants. Ratios of product yields ([P1]/[P2]) from reactions at 25 °C were
calculated from the ratio of peak areas determined by HPLC analysis
(A1/A2) and the ratio of extinction coefficients, (ꢀP2/ꢀP1), at 274 nm using
eq 1. The reproducibility of the product ratios from HPLC analysis
was ( 10%
[P1]
[P2]
A1 ꢀP2
)
(1)
(2)
(A )(ꢀ )
2
P1
kNu1
[1 - Nu1][Nu2]
[1 - Nu2][Nu1]
)
kNu2
Kinetic Studies. The specific acid-catalyzed solvolysis reactions of
1-OPh at 25 °C in 50:50 (v:v) trifluoroethanol/water were initiated by
making a 100-fold dilution of a solution of substrate dissolved in
acetonitrile into the mixed solvent containing acetonitrile to give a final
concentration of 0.4 mM. The reaction progress was monitored
spectrophotometrically at 25 °C by following the increase in absorbance
at 269 nm. First-order rate constants, kobsd (s-1), for solvolysis were
determined as the slopes of semilogarithmic plots of reaction progress
against time, which in all cases were linear for at least three-halftimes.
Rate constant ratios for the reactions of nucleophiles Nu1 and Nu2
with 1-Y were calculated directly from the ratios of product con-
centrations using eq 2 with the exception of the reactions of 1-(3,5-
dinitrobenzoate) described below. The following extinction coefficients
at 274 nm in 70/30 (v/v) methanol/water were determined from the
absorbance of known concentrations of synthetic standards [ꢀ, (M-1
cm-1)]: 1-OH, 1400; 1-OPh, 2550; 1-(4-C6H4OH), 2850; 4-methoxy-
styrene, 11 000. The value of ꢀ1-(2-C6H4OH)/ꢀ1-(4-C6H4OH) ) 1.28 at 274
nm was determined from the ratio of peak areas from HPLC analysis
of a mixture of 1-(2-C6H4OH) and 1-(4-C6H4OH) and the ratio of the
concentration of these compounds determined from the ratio of the 1H
NMR peak areas of the methine protons. Combining this ratio with ꢀ
) 2850 M-1 cm-1 for 1-(4-C6H4OH) gives ꢀ ) 3650 M-1 cm-1 for
1-(2-C6H4OH). It has been shown that the extinction coefficients for
1-OH, 1-OCH2CF3, and 1-N3 are identical at λmax for 1-OH.12
The yields of the products of reactions of 1-(3,5-dinitrobenzoate)
in 48/2/50 (v/v/v) trifluoroethanol/phenol/water (I ) 0.50, NaClO4) that
contain 4-5 mM NaN3 and increasing concentrations of lyoxide ion
were determined by HPLC analysis. The final concentrations of
CF3CH2O- and PhO- in this mixed solvent were determined by the
following procedure.23a
[CF3CH2OH]
[1 - Nu]
Keq
)
(5)
(6)
(
[1 - OCH CF ]) (
)
[PhOH]
2
3
eq
Σ (AP/ꢀP)
(AS)i/ꢀS
Σ [P]
[S]o
)
) kobsdt
[
]
The reactions of 1-OPh (2 mM) in 50/50 (v/v) trifluoroethanol/water
that contained 20 mM sodium carbonate or sodium phosphate buffer
were monitored by HPLC, using ca. 10 µM of the internal standard
fluorene to correct for small variations in the sample volume analyzed
by HPLC. First-order rate constants, kobsd (s-1) were determined as the
slopes of linear plots of reaction progress against time over the first
2-8% of the reaction using eq 6 where; (a) Σ(AP/ꢀP) is the sum of the
concentrations of all of the reaction products, calculated from their
respective HPLC peak areas (AP) and extinction coefficients (ꢀP) at 274
nm, and (b) (AS)i/ꢀS is the initial concentration of the substrate 1-OPh.
Ab Initio Calculations. The relative energies of 1-OPh and 1-(2-
C6H4OH) were determined by ab initio calculations using Gaussian
92.4.25 The geometries of the two species were fully optimized at the
Hartree-Fock (HF) level using the 6-31G(d) basis set.26 The two
structures were fully characterized as energy minima by vibrational
(A1-OH obsd
)
(A1-OTFE TFEO
)
) (A1-OTFE obsd
)
-
(3)
(4)
[
]
7.6
(A1-OTFE TFEO
)
kaz
-
[CF3CH2O-] )
[N3
]
-
(
)(k
)
(A1-N3
)
TFE
(1) The concentration of [CF3CH2O-] was determined from the
excess yield of 1-OCH2CF3 over that observed when [CF3CH2O-] )
0 M, using eqs 3 and 4 where, (a) The relative yields of 1-OH,
1-OCH2CF3, and 1-N3 can be obtained directly from the relative product
peak areas, which have the same extinction coefficient at 274 nm. (b)
(23) (a) These solutions were prepared by adding sodium hydroxide to a large
excess concentration of phenol (0.23 M, pKa ) 10.0) and trifluoroethanol
(6.6 M, pKa ) 12.4). The conversion of hydroxide ion to trifluoroethoxide
and phenoxide ion was essentially quantitative, because phenol and
trifluoroethanol are much stronger acids than water (pKa ) 15.7). (b) The
apparent rate constant ratios for addition of water and azide ion to 1-OPh
to form 1-OH and 1-N3 respectively, calculated from data in Table 1, remain
constant within the experimental error (( 10%) as [NaOH]t is increased
from 0 to 0.083 M. This shows that there is no significant formation of
1-OH by (i) Addition of hydroxide ion to the carbocation reaction
intermediate 1+,12 because there is essentially quantitative protonation of
hydroxide ion by phenol and trifluoroethanol and (ii) Addition of solvent
anion (hydroxide, trifluoroethoxide or phenoxide ion) to the carbonyl group
of 1-(3,5-dinitrobenzoate).
(A1-OTFE
)
is the area of the peak for 1-OCH2CF3 that forms from
TFEO
the reaction of CF3CH2O-. (c) (A1-OTFE
peak for 1-OCH2CF3 from HPLC analysis. (d) (A1-OH
area of the peak for 1-OCH2CF3 that forms by reaction of neutral
)
obsd is the observed area of the
obsd/7.6 is the
)
CF3CH2OH, calculated from the area of the peak for 1-OH (A1-OH
)
(21) Richard, J. P. J. Am. Chem. Soc. 1989, 111, 1455-1465.
(22) Difficulties were experienced in obtaining baseline separation of the large
peak for phenol cosolvent from the peaks for the reaction products which
were present in much smaller concentrations. Satisfactory separations were
observed using the relatively large substrate concentration of 2 mM 1-(3,5-
dinitrobenzoate) and a 10 µL injection volume.
(24) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1373-1383.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15457

A R T I C L E S
Tsuji et al.
Table 1. Yield of Products Determined by HPLC Analyses of the Reaction of 1-(3,5-Dinitrobenzoate) in 48/2/50 (v/v/v) TFE/PhOH/H2O in
Basic Solutions that Contain Azide Iona
[N -
M
]
[NaOH]t
M b
[PhO-]
M c
1-OH
%
1-OCH CF
Styrened
%
1-N
%
1-OPh
%
1-(2-C H OH)
1-(4-C H OH)
3
2
3
3
6
4
6
4
%
%
%
0.005
0
0
55.9
42.4
31.5
25.0
12.6
7.5
5.8
5.5
4.9
5.2
0.021
0.11
0.17
0.21
0.29
32.1
21.9
16.7
10.6
5.3
4.2
13.6
19.8
24.6
31.1
0.018
5.8
9.3
12.3
16.4
0.21
10.5
17.0
22.4
29.0
0.0049
0.0048
0.0047
0.0042
0.0083
0.017
0.033
0.083
0.0079
0.0132
0.027
0.058
a For reactions at 25 °C in 50/50 (v/v) trifluoroethanol/water (I ) 0.50, NaClO4). b [NaOH]t is the concentration, after dilution, of sodium hydroxide
used to prepare this solution. c The concentration of phenoxide ion that is formed by deprotonation of hydroxide ion, calculated as described in the text.
d4-Methoxystyrene.
frequency calculations. In both cases, the computed harmonic vibrational
frequencies are all positive. Electron correlation effects were included
through single-point energy calculations at the hybrid DFT B3LYP/
6-31G(d) level27,28 using the HF/6-31G(d) geometries. Solvation effects
were examined using the isodensity surface polarizable continuum
model (IPCM) by single-point energy calculations at the B3LYP/
6-31G(d)//HF/6-31G(d) level.29 A dielectric constant of 78.4 was used
to represent the solvent water.
Results
The product yields from the reaction of 2 mM 1-(3,5-
dinitrobenzoate) in 48/2/50 (v/v/v) trifluoroethanol/phenol/
water (I ) 0.50, NaClO4) that contained 5.0 mM NaN3 and
either 5 mM or 10 mM NaOAc were determined by HPLC
analyses and are reported in Table 1. These product yields were
determined after one to two reaction halftimes, at which point
no more than 10% of the azide ion was consumed in forming
the azide ion adduct 1-N3.22 The slow cleavage of 1-OPh
Figure 1. Effect of increasing concentrations of LCl on kobsd (s-1) for
catalyzed by the 3,5-dinitrobenzoic acid product was noted in
early experiments. Therefore, these reactions were run in the
presence of a small concentration of acetate ion in order to
neutralize this carboxylic acid. 1-OPh was stable under these
reaction conditions. Identical product yields were observed for
reactions in the presence 5.0 and 10 mM acetate ion.30
The yield of products from the reaction of 1-(3,5-dinitroben-
zoate) in solutions of 48/2/50 (v/v/v) trifluoroethanol/phenol/
water (I ) 0.50, NaClO4) that contain 4-5 mM NaN3 and
increasing concentrations of phenoxide ion are also reported in
Table 1. The basic solvents were prepared by mixing aqueous
sodium hydroxide with 96/4 (v/v) trifluoroethanol/phenol. Table
1 reports values for [NaOH]t, the concentration of NaOH (after
dilution) used to prepare the mixed solvent. The concentrations
of phenoxide ion in these solutions were then calculated as the
difference between [NaOH]t and the value of [CF3CH2O-] as
described in the Experimental section.23a,b
solvolysis of 1-OPh in 50/50 (v/v) CF3CH2OH/H2O (HCl, b) and in 50/50
(v/v) (v/v) CF3CH2OD/D2O (DCl, 1) at 25°C and I ) 0.50 maintained
with NaClO4.
The solvolysis of 1-OPh was monitored by following the
decrease in absorbance at 269 nm. Figure 1 shows the increase
in kobsd (s-1) for solvolysis of 1-OPh that was determined at
increasing [HCl] or [DCl] for reactions in 50/50 (v/v) CF3CH2-
OH/H2O (HCl) and in 50/50 (v/v) CF3CH2OD/D2O (DCl) at
25°C (I ) 0.50, NaClO4). Values of kH ) 0.55 and kD ) 1.37
M-1 s-1 for specific-acid catalysis of solvolysis of 1-OPh in
H2O and D2O, respectively, were determined from the slopes
of these plots.
The products of the reaction of 1-OPh in 50/50 (v/v)
trifluoroethanol/water at 25 °C (I ) 0.50, NaClO4) and in
solutions of increasing pH were determined by HPLC analysis.
Values of kobsd (s-1) for the reaction of 1-OPh and the yields
of the reaction products are reported in Table 2. The values of
pHw reported in Table 2 are the observed pH of the buffers in
water, before mixing with the trifluoroethanol cosolvent. The
reaction of 1-OPh in 48/2/50 (v/v/v) trifluoroethanol/phenol/
water that contained 0.012 M HClO4 (I ) 0.50, NaClO4) was
monitored by HPLC. Solvolysis of 1-OPh to form 1-OCH2CF3
and 1-OH is much faster than formation of 1-(4-C6H4OH)
and 1-(2-C6H4OH). The ratio of the concentrations of the
former compounds decreases to a limiting value of ([1-OPh]/
[1-OCH2CF3])eq ) 0.10 after a reaction time of 1 day. This
ratio then remains constant as 1-OPh, 1-OCH2CF3, and 1-OH
undergo slower conversion to 1-(4-C6H4OH) and 1-(2-
C6H4OH). Combining ([1-OPh]/[1-OCH2CF3])eq ) 0.10 with
the ratio of the concentration of the reactants (eq 5) gives KO
) 0.29 for conversion of 1-OCH2CF3 to 1-OPh (Scheme 3).
(25) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; J. A. Montgomery, J.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Salvador, P.;
Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B.
B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M.
W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A.; Gaussian 92.4; Gaussian, Inc: Pittsburgh, PA, 2001.
(26) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular
Orbital Theory; John Wiley & Sons: New York, 1986.
(27) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. 1988, B37, 785-789.
(28) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(29) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239.
(30) The yield in these reactions of 1-OAc from the reaction of acetate ion was
< 1%.
9
15458 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Barriers to C and O Alkylation of Phenol
A R T I C L E S
Table 2. First-Order Rate Constants and Product Yields for
Solvolysis of 1-OPh in 50/50 (v/v) Trifluoroethanol/Watera
correction of the relative energy difference to 1.3 kcal/mol. The
free energies of solvation of 1-(2-C6H4OH) and 1-OPh by water
were calculated using a continuum solvation model to be -5.4
kcal/mol and -2.0 kcal/mol respectively, which corresponds
to 3.4 kcal/mol more favorable solvation of the former
compound. Combining the 1.3 kcal/mol difference in the
stability of 1-(2-C6H4OH) and 1-OPh in the gas phase with
the 3.4 kcal/mol difference in the free energy for solvation by
productsd
1-OH 1-OCH CF 1-(2-C H OH) 1-(4-C H OH)
2
3
6
4
6
4
buffer
pHwb
k
obsd/s-1c
%
%
%
%
phosphate 7.8 13.5 × 10- 9 80.5
8.6
7.9
7.4
6.6
8.0
6.3
13.7
17.8
28.7
29.2
4.6
10.0
13.0
19.5
19.8
8.3 6.3 × 10- 9 68.4
8.5 4.9 × 10- 9 61.8
carbonate 9.0 2.9 × 10- 9 45.1
o
10.0 2.9 × 10- 9 43.1
water gives ∆Giso ) -4.7 kcal/mol for the isomerization of
1-OPh to 1-(2-C6H4OH) in water (Scheme 3).
a For reactions at 25 °C in 50/50 (v/v) trifluoroethanol/water (I ) 0.50,
NaClO4). b The initial pH of the buffered aqueous solution, prior to mixing
with an equal volume of trifluoroethanol. c The first-order rate constant for
solvolysis of 1-OPh, determined by the method of initial rates. d The product
yields were determined by HPLC analyses.
Discussion
1-(4-Methoxyphenyl)ethyl derivatives undergo solvolysis in
mixed aqueous/organic solvents by a DN + AN (SN1)31 reaction
mechanism through a “liberated” carbocation intermediate 1+
which partitions between the diffusion-limited addition of azide
ion and the slower addition of solvent.12,32 Rate constants for
addition of the different nucleophilic sites of phenol to 1+
(Scheme 4) may be determined from the product rate constant
ratios kaz/kNu (eq 2) and kaz ) 5 × 109 M-1 s-1 for the diffusion-
limited reaction of azide ion.12,15,32
Scheme 3
Addition of Phenol to 1+. The reaction of 1-(3,5-dini-
trobenzoate) in 48/2/50 (v/v/v) trifluoroethanol/phenol/water
(I ) 0.50, NaClO4) in the presence of azide ion at neutral pH
gives seven products, whose yields are reported in Table 1.
Three of these products are from addition of phenol to 1+;
1-OPh, 1-(2-C6H4OH) and 1-(4-C6H4OH) (Scheme 4); three
are from addition of other nucleophiles: 1-OH, 1-OCH2CF3,
and 1-N3; and, a small yield of 4-methoxystyrene forms by
deprotonation of 1+ in a reaction that is not shown in Scheme
4 (e 0.3%).
Table 3. Calculated Relative Energies of 1-OPh and
1-(2-C6H4OH)
The left-hand side of Table 4 reports rate constant ratios for
calculation
partitioning of 1+ between addition of trifluoroethanol (kTFE
)
compd
1-OPh a
1-(2-C6H4OH) b
HF/6-31G(d)
B3LYP/6-31G(d)
IPCM/B3LYP/6-31G(d)
and phenol (k°O, k°para and k°otho, Scheme 4) determined from
the ratio of product yields (eq 2) and absolute rate constants
calculated from these rate constant ratios using kTFE ) 8 × 105
0.0
0.0
0.0
-1.9 (-1.7)c
-1.5 (-1.3)c
-4.9 (-4.7)c
M-1 -1 12,15
The ca. 20-fold larger yield of the oxygen compared
s
.
a Total energies for the O-adduct are -727.04713, -731.65820, and
-731.66146 hartrees at the HF/6-31G(d), B3LYP/6-31G(d), and IPCM/
B3LYP/6-31G(d) level, respectively. The difference in energy between the
continuum IPCM and B3LYP calculations gives the difference in the free
energy of solvation of 1-OPh and 1-(2-C6H4OH). b The difference in
kcal/mol between the energies for formation of 1-(2-C6H4OH) and 1-OPh.
c The computed change in Gibbs free energy that includes the changes in
entropy and enthalpy for reaction at 298 K.
to carbon adducts for addition of phenol shows that the hydroxyl
group of phenol is more nucleophilic than the ring carbons
toward 1+ in a mostly aqueous solvent. The nucleophilic
reactivity of the para carbon of phenol is 11-fold greater than
the ortho-carbon, possibly because of greater steric hindrance
to reaction of the ortho-carbon.
Mechanism for Oxygen Alkylation of Phenol. The second-
order rate constants for addition of alkyl alcohols to 1+ increase
with increasing alcohol pKa and these data are correlated by
the Brønsted coefficient of ânuc ) 0.32 (Figure 2A).24 The rate
constant kROH for addition to 1+ of a hypothetical alkyl alcohol
with the same pKa ) 10 as for phenol, obtained by extrapolation
of the linear Brønsted correlation (Figure 2A), is 6-fold smaller
than kTFE for addition of trifluoroethanol. By comparison, the
rate constant kPhOH for addition of phenol is 16-fold greater than
The reaction of 1-OH at 25 °C in 50/50 (v/v) trifluoroethanol/
water that contained 0.50 M perchloric acid (I ) 0.50, NaClO4)
and 18 mM phenol was monitored by HPLC over a period of
7 days. At the end of this time the conversion of 1-OH to 1-(2-
C6H4OH) and 1-(4-C6H4OH) was essentially quantitative, and
there was no sign that equilibrium had been achieved. The ratio
of the concentrations of 1-OCH2CF3, 1-(2-C6H4OH), and 1-(4-
C6H4OH) at the time when 1-OCH2CF3 could just be detected
by HPLC analysis is 1:25:114. Combining [1-OCH2CF3]/
[1-(2-C6H4OH)] ) 25 and [TFE]/[Phenol] ) 380 gives a lower
limit of Kortho > 9500 (Scheme 3). The values of Kortho and KO
were combined to give Kiso ) Kortho/KO > 9500/0.29 > 33 000
for isomerization of 1-OPh to 1-(2-C6H4OH).
kTFE (Table 4), which corresponds to a 2.0 unit positive deviation
of log kPhOH from this Brønsted correlation.
The larger reactivity of the aryl alcohol (phenol) compared
with alkyl alcohols toward 1+ is due to either: (1) a stabilizing
interaction that is expressed at the ether product 1-OPh and to
an equal or smaller extent at the transition state for formation
1-(2-C6H4OH) was calculated to be 1.7 kcal/mol more stable
than 1-OPh in the gas phase at the HF/6-31G(d) level (Table
3). The inclusion of electron correlation effects at the higher
B3LYP/6-31G(d) level of theory leads to a small 0.4 kcal/mol
(31) Guthrie, R. D.; Jencks, W. P. Acc. Chem. Res. 1989, 22, 343-349.
(32) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4689-4691.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15459

A R T I C L E S
Tsuji et al.
Scheme 4
Table 4. Product Rate Constant Ratios and Absolute Rate Constants for Addition of Phenol and Phenoxide Ion to 1+a
reacting atom
reacting atom
(kNu)b
kNu/kTFE
16
kNud M-1s-1
1.3 × 107
kO/kCf
nucleophile
(kNu)b
kNu/kaz
0.39
kNue M-1s-1
2 × 109
kO/kCf
c
c
nucleophile
oxygen
(k°O)
p-carbon
oxygen
(k-
)
O
( 0.007
0.41
( 0.008
0.22
0.8
0.07
6 × 105
6 × 104
20
p-carbon
2 × 109
1 × 109
1.0
0.5
(k°ortho
o-carbon
(k°para
)
(k-
)
ortho
230
o-carbon
)
(k-
)
( 0.005
para
a For reactions at 25 °C in 50/50 (v/v) trifluoroethanol/water (I ) 0.50, NaClO4). b The rate constants kNu defined in Scheme 4. c Product rate constant
ratio for partitioning of 1+ between addition of trifluoroethanol and the different nucleophilic sites of phenol or phenoxide ion. The reported errors are the
standard deviations from these linear correlations. d Absolute rate constants determined from the product rate constant ratio and kTFE ) 8 × 105 M-1s-1 (ref
e
f
12). Absolute rate constants determined from the product rate constant ratio and kaz ) 5 × 109 M-1s-1 (ref 12). Rate constant ratio for addition of the
nucleophilic oxygen and carbon of phenol or phenoxide ion.
Scheme 5
) PhOH, Scheme 5) for conversion of 1-OCH2CF3 to 1-OPh
lies on a linear logarithmic correlation of log KROH against the
pKa of other alkyl alcohols34a (Figure 2B) shows that there is
no special stabilization of 1-OPh in comparison with alkyl ethers
1-OR. We conclude that the enhanced reactivity of phenol
compared with alkyl alcohols reflects the smaller Marcus
intrinsic barrier for addition of phenol. The smaller intrinsic
barrier for formation of aryl compared to alkyl ethers is
manifested in the cleavage direction by the larger second-order
rate constant for acid-catalyzed cleavage of 1-OPh (kH ) 0.55
M
-1-s-1, this work) than for cleavage of 1-OMe (kH ) 0.038
M-1-s-1).34b
The lower intrinsic barrier for addition of phenol than for
addition of alkyl alcohols to 1+ might be due to a more shallow
curvature along the reaction coordinate for stepwise addition
of the former nucleophile to form the protonated ether prod-
uct.33,35 However, we are unable to provide a rationalization
for such a difference in the shape of reaction coordinates for
addition of alkyl and aryl alcohols by a common reaction
mechanism. Alternatively, the high nucleophilic reactivity of
phenol may reflect a change from a stepwise mechanism to a
Figure 2. Brønsted correlations of rate and equilibrium constants for
addition of alkyl alcohols (b) and phenol (2) to 1+ in 50/50 (v/v) tri-
fluoroethanol/water at 25 °C and I ) 0.50 maintained with NaClO4. A.
Correlation of second-order rate constants for nucleophilic addition of alkyl
24
alcohols. B. Correlation of dimensionless equilibrium constants for the
34a
reaction of alkyl alcohols shown in Scheme 5.
of 1-OPh; or (2) a stabilizing interaction that is unique to the
transition state and that results in a lower Marcus intrinsic barrier
for addition of aryl compared with alkyl alcohols.33 The
observation that the equilibrium constant KROH ) 0.29 (ROH
(34) (a)Rothenberg, M. E.; Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc.
1985, 107, 1340-1346. (b) Footnote 59 of ref 18.
(35) Jencks, W. P. Bull. Soc. Chim. Fr. 1988, 218-224.
(33) Richard, J. P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001, 34,
981-988.
9
15460 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Barriers to C and O Alkylation of Phenol
A R T I C L E S
Scheme 6
Scheme 7
Chart 1
2-OPh,39 where the leaving group is weakly basic phenol, is
consistent with a change to a concerted reaction mechanism,
and the attenuation of the inverse solvent isotope effect by a
primary deuterium isotope effect for a reaction in which proton
transfer and C-O bond cleavage are coupled. There must be
the same difference in the mechanism for addition of the aryl
alcohol phenol and the alkyl acohol methanol to the oxocarbe-
nium ion 2+ for reaction in the reverse direction.
stepwise-preassociation or concerted (Scheme 6) mechanism for
addition of phenol to 1+. This proposal is consistent with the
following observations:17,36-40 (1) There is good evidence that
the addition of alkyl alcohols to carbocations17,41 and to
oxocarbenium ions42,43 proceeds by a stepwise mechanism
through an oxonium ion intermediate. The decrease in the pKa
of the alkyl alcohol nucleophile from 12.4 for trifluoroethanol
to 10 for the aryl alcohol phenol will favor a change to a
concerted mechanism for the uncatalyzed reaction (Scheme 6).
This is because the change to a more weakly basic alcohol
oxygen will cause a destabilization of the protonated ether
reaction intermediate that will favor the concerted reaction
mechanism that avoids its formation.17,40 (2) There is a change
from no detectable catalysis by carboxylic acids, to a substantial
rate acceleration from concerted general acid catalysis, as the
alkyl alcohol leaving group is changed from strongly to weakly
basic for solvolytic cleavage of substituted benzaldehyde acetals
to form an oxocarbenium ion.36 Likewise, in the reverse
carbocation-nucleophile addition direction there is a change
from no detectable catalysis by carboxylate ions of alkyl alcohol
addition to 1+, to an easily observed Brønsted general base
catalyzed reaction as the alcohol is changed from ethanol to
trifluoroethanol. These observations show that the change to a
more weakly basic leaving group/nucleophile should favor a
concerted mechanism for reversible water “catalyzed” formation
of 1+ from 1-OR. (3) The solvent deuterium isotope effect of
kH/kD ) 0.33 on specific acid-catalyzed solvolysis of 4-meth-
oxybenzaldehyde dimethyl acetal39 (Chart 1) is consistent with
equilibrium protonation of 2-OMe, which shows a large inverse
equilibrium solvent deuterium isotope effect, followed by the
rate determining C-O bond cleavage to form 2+ for which there
can be no more than a small primary solvent isotope effect.
The increase to kH/kD ) 0.65 for cleavage of the mixed acetal
In summary, these results show that there is a specific
stabilization of the transition state for addition of weakly basic
phenol compared to alkyl alcohols to 1+, and, they are consistent
with a change from a stepwise to concerted mechanism (Scheme
6) that has been observed to occur for related reactions as the
leaving group/nucleophile is made more weakly basic. However,
the solvent deuterium isotope effect of kH/kD ) 0.40 for specific-
acid-catalyzed cleavage of 1-OPh in 50/50 (v/v) trifluoroethanol/
water (Figure 1) is only marginally larger than kH/kD ) 0.33
for stepwise cleavage of 2-OMe in water. This shows that the
transition state for acid-catalyzed cleavage of 1-OPh is similar
to that for the fully stepwise mechanism, where the protonated
phenyl ether is “trapped” by deprotonation by solvent (k1, kr,
kp, Scheme 7). It suggests that the cleavage of 1-OPh might
proceed by a stepwise preassociation mechanism (Kas, k1′, kp,
Scheme 7):44-46 the advantage of the preassociation pathway
compared to the fully stepwise “trapping” is due to stabilization
of the rate-determining transition state for k1′ by the hydrogen
37,45
bond to solvent.
There must be the same favored, low free-energy pathway
for formation and breakdown of 1-O(H)Ph+ that is hydrogen
bonded to water (Scheme 7).44-46 Therefore, the relative barriers
for the stepwise “trapping” and for the stepwise preassociation
reaction mechanism in the direction of cleavage of 1-OPh are
determined by the relative values of k-r for cleavage of this
hydrogen bond and k-1′ for heterolytic ionization to form
1+.44-46 The value of k-r is smaller than the maximum value
of 1011 s-1 for the reorganization of solvent,47-49 because the
substantial barrier to cleavage of the strong hydrogen bond
between water and 1-O(H)Ph+ should lower this rate constant
by 100-fold or more.50 An estimate k-1′ ≈ k-1 ≈ 7 × 107 s-1
can be obtained using the relationship k-1 ) kHKa, where kH )
0.55 M-1 s-1 is the second-order rate constant for specific acid-
(36) Jensen, J. L.; Herold, L. R.; Lenz, P. A.; Trusty, S.; Sergi, V.; Bell, K.;
Rogers, P. J. Am. Chem. Soc. 1979, 101, 4672-4677.
(37) Jencks, W. P. Acc. Chem. Res. 1976, 9, 425-432.
(38) Bunton, C. A.; Davoudazedeh, F.; Watts, W. E. J. Am. Chem. Soc. 1981,
103, 3855-3858.
(44) Gilbert, H. F.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 7931-7947.
(45) Jencks, W. P. Chem. Soc. ReV. 1981, 10, 345-375.
(46) Thibblin, A.; Jencks, W. P. J. Am. Chem. Soc. 1979, 101, 4963-4973.
(47) Giese, K.; Kaatze, U.; Pottel, R. J. Phys. Chem. 1970, 74, 3718-3725.
(48) Kaatze, U. J. Chem. Eng. Data 1989, 34, 371-374.
(49) Kaatze, U.; Pottel, R.; Schumacher, A. J. Phys. Chem. 1992, 96, 6017-
6020.
(39) Capon, B.; Nimmo, K. J. Chem. Soc., Perkin Trans. 2 1975, 1113-1118.
(40) Ta-Shma, R.; Jencks, W. P. J. Am. Chem. Soc. 1986, 108, 8040-8050.
(41) Gandler, J. R. J. Am. Chem. Soc. 1985, 107, 7.
(42) Fife, T. H. AdV. Phys. Org. Chem. 1975, 11, 8218-8223.
(43) Cordes, E. H.; Bull, H. G. Chem. ReV. 1974, 74, 581-603.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15461

A R T I C L E S
Tsuji et al.
catalyzed cleavage of 1-OPh and Ka ≈ 108.1 M-1 51 is the acidity
constant for 1-O(H)Ph+. We conclude that the values of k-1
′
and k-r from Scheme 7 are similar. However, it is not possible
to rigorously demonstrate that the preassociation reaction
mechanism is viable, because of the uncertainty in the acidity
constant Ka for 1-O(H)Ph+ and in the rate constant k-r for
hydrogen bond cleavage.
If the reaction proceeds by a concerted mechanism that avoids
formation of the protonated intermediate, then the inverse
solvent deuterium isotope effect of kH/kD ) 0.40 would require
that proton transfer from hydronium ion be essentially complete
at a transition state which shows a strong similarity to the
protonated intermediate 1-O(H)Ph+. Therefore, for either the
stepwise preassociation or concerted mechanism, the 3 kcal/
mol advantage for addition of phenol compared with the fully
stepwise addition of alkyl alcohols, that can be calculated from
the 2 unit positive deviation of log kPhOH from the Brønsted
correlation shown in Figure 2A must be due mainly to
stabilization of this transition state by hydrogen bonding to the
hydronium ion catalyst.
Figure 3. The effect of increasing the ratio of the concentrations of reactants
phenoxide and azide ion ([PhO-]/[N3-]) on the ratio of the yields of the
products of solvolysis of 1-(3,5-dinitrobenzoate) in 50/50 (v/v) trifluoro-
ethanol/water at 25°C and I ) 0.50 maintained with NaClO4: (2), ROPh
) 1-OPh; (b), ROPh ) 1-(4-C6H4OH); (1), ROPh ) 1-(2-C6H4OH).
Addition of Phenoxide Ion to 1+. The rate constant ratios
k-O/kaz, k-para/kaz, and k-ortho/kaz for addition of phenoxide ion
to 1+ to form 1-OPh, 1-(4-C6H4OH), and 1-(2-C6H4OH),
respectively, (Scheme 4) were determined as the slopes of linear
correlations (Figure 3) of the ratio of product yields [1 - Nu]/
[1 - N3] against the ratio of the nucleophile concentrations
according to eq 7, where Ro is the limiting ratio observed for
the reaction in a neutral solution. Combining these ratios with
kaz ) 5 × 109 M-1 s-1 for the diffusion-limited reaction of
for addition of the different nucleophilic sites of phenoxide ion
to 1+ (2:2:1, Table 4) is much smaller than that for addition of
the same nucleophilic sites of phenol (230:20:1). This is
consistent with a large Hammond-type shift toward a very
“early” transition state for addition of strongly nucleophilic
phenoxide ion to 1+.52
Nucleophilicity of Phenol Carbon. Equation 8 has been
shown by Mayr and co-workers to correlate data for a large set
of carbon nucleophiles.53-55 Values of N ) 1.9 and 0.9,
respectively, for the reaction of the para- and ortho-carbons of
phenol can be calculated from eq 8 using E ) 3.9 for the
electrophilicity parameter and s ≈ 1 for addition of carbon
nucleophiles to carbocations,53 where E ) 3.9 was also
calculated from eq 8, using kNu ) 1 × 108 s-1 12 for addition of
water to 1+, and N ) 5.1 and s ) 0.89 for addition of water to
carbon electrophiles.55
azide ion gives the values for kNu ) k--O, k-para, or k-
ortho
reported in Table 4.
kNu[PhO-]
[1 - Nu]
)
+ Ro
(7)
-
(
)
[1 - N3]
kaz[N3 ]
The sum of the ratios for partitioning of 1+ between carbon
and oxygen alkylation of phenoxide ion (k-O + k-para + k-ortho)/
kaz is equal to 1.0, and the total rate constant for addition of
phenoxide ion [kPhO ) k-O + k-para + k-ortho] is equal to kaz
)
log kNu ) s(N + E)
(8)
5 × 109 M-1 s-1 for the diffusion-limited reaction of azide
ion.12,15,32 We conclude that the addition of phenoxide to 1+
proceeds by fast and effectively irreVersible formation of a
carbocation-anion pair that partitions between reaction with
the three nucleophilic sites of phenoxide ion with a net rate
constant that is greater than the rate constant for separation of
the ion pair to free ions (k-d ≈ 1.6 × 1010 s-1).24 The selectivity
The value of N ) 1.9 for alkylation of the para carbon of
53
54
phenol falls between the values of N ) -1.6
and 3.7
reported for alkylation of methoxybenzene and aniline, respec-
tively. This shows that activation of the phenol ring for reaction
as a nucleophile by an -OH group is between the activation
by -OCH3 and -NH2 groups, and is consistent with the relative
values of Hammett substituent constant σR ) (σ+ - σn)
(50) The rate constant ratio kr/k-r defines the strength of the hydrogen bond
between the very strong acid 1-O(H)Ph+ (pKa ≈ -8.1, ref 51) and water.
A value of kr/k-r ) 100 would correspond to ∆G° ≈ -2.7 kcal/mol for
stabilization of 1-O(H)Ph+ by a hydrogen bond to solvent. By comparison,
the hydrogen bond between water and the -OH group of the 4-hydroxy-
benzyl carbocation (pKa ) -2) provides a 4 kcal/mol stabilization of this
carbocation toward addition of water to form 4-hydroxybenzyl alcohol,
compared with addition of water to the 4-methoxybenzyl carbocation to
form 4 methoxybenzyl alcohol [M. M. Toteva; M. Moran; T. L. Amyes; J.
P. Richard J. Am. Chem. Soc. 2003, 125, 8814-8819.
determined for these groups; σR
OMe
) -1.2, σR ) -0.75,
NH2
OH
σR
) -0.66.56
Encounter-Limited Reactions of Alkoxide and Aryloxide
Anions. Phenoxide ion is a rare example of a carbon nucleophile
that undergoes diffusion-controlled addition to 1+ with a rate
constant similar to that for the very good inorganic nucleophile
azide ion. The ratio of kNu/kaz ) 1.0 determined by analysis of
the products of partitioning of the R-(N,N-dimethylthiocar-
(51) The pKa for 1-O(H)Ph+ is estimated from pKa ) -3.4 for 1-O(H)Me+,
with the assumption that the phenyl for methyl substitution will have the
same 4.69 unit effect on this pKa as for phenyl substitution at trimethyl-
ammonium ion (pKa ) 9.76) to give dimethylanilinium ion (pKa ) 5.07).
The pKa for 1-O(H)Me+ was estimated from pKa ) -2.52 for protonated
dimethyl ether (Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano,
G. J. Am. Chem. Soc. 1973, 95, 5960-5964), σI ) 0.11 and σI ) -0.01
for the 4-MeOC6H4- and Me- substituents respectively [Charton, M. Prog.
Phys. Org. Chem. 1981, 13, 119-251], and, FI ) 8.75 [footnote 9 of ref
68] for ionization of alcohols of structure R1R2CHOH.
(52) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334-338.
(53) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957.
(54) Mayr, H.; Kempf, B.; Ofial, A. Acc. Chem. Res. 2003, 36, 66-77.
(55) Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125, 286-295.
(56) Hine, J. Structural Effects on Equilibria in Organic Chemistry; Wiley: New
York, 1975.
9
15462 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Barriers to C and O Alkylation of Phenol
A R T I C L E S
Scheme 8
Table 5. Limiting Rate Constants for Encounter-Limited Addition
of Nucleophilic Anions to Ring-Substituted 1-Phenylethyl
Carbocationsa
(kNu)lim/M-1 s-1 c
b
nucleophile
pK
a
(kNu/kaz)lim
- d
CH3CO2
4.8
10.0
12.4
0.10
5 × 108
5 × 108
PhO- e
1.0f(0.4)g
0.10
5 × 109 f(2 × 109)g
CF3CH2O- d
a For reactions at 25 °C in 50/50 (v/v) trifluoroethanol/water (I ) 0.50,
NaClO4). b The limiting partition rate constant ratio for encounter-limited
addition of azide ion and the nucleophilic oxyanion. c The limiting rate
constant for encounter-limited addition of the oxyanion, calculated from
the partition rate constant ratio and kaz ) 5 × 109 M-1 s-1 for the diffusion-
limited reaction of azide anion. d Data from ref 24. eThis work. fThe value
of kNu/kaz or kNu calculated as the sum of the rate constants for reaction of
g
the three nucleophilic sites of phenoxide ion. The value of kNu/kaz or kNu
for oxygen addition of phenoxide ion.
bamoyl)-4-methoxybenzyl carbocation between addition of
2-(dimethylamino)-6-methoxybenzothiophene and azide ion
provides a second example of a carbon nucleophile with a
reactivity comparable to that for azide ion.19,20
the diffusion-controlled limit and then partitions between
addition of the ring carbon atoms to 1+ and desolvation at
oxygen followed by oxygen addition (Scheme 8B). The
relatively low barrier to desolvation of phenoxide ion within
the initial ion-pair might reflect the disruption of the solvation
shell about phenoxide ion that occurs with the development of
stabilizing hydrophobic interactions between the aromatic ring
of phenoxide ion and 1+.
The rate constants for addition of azide and thiolate anions
to ring-substituted 1-phenylethyl carbocations increase up to the
diffusion-controlled limit (kNu ) kd ) 5 × 109 M-1 s-1) as the
carbocation is destabilized by electron-withdrawing ring sub-
stituents,12,14,24,57 but the “limiting” rate constant for encounter-
controlled addition of acetate and trifluoroethoxide anion to ring-
substituted 1-phenylethyl carbocations is ∼10-fold smaller than
for a simple diffusion-limited reaction.24 These small rate
constants for encounter-controlled reactions provide evidence
that formation of encounter complexes between carbocations
and oxygen-anions in water is limited in some way by rate of
desolvation of the nucleophilic anion.
Reactions of Intimate Ion Pairs and Ion-Dipole Pairs.
The perchloric-acid-catalyzed cleavage of 1-OPh in 50/50
(v/v) trifluoroethanol/water gives only 1-OH and 1-OCH2CF3
and no detectable 1-(4-C6H4OH) and 1-(2-C6H4OH) from
reaction of an ion-dipole pair (idp).12 This is because the phenol
leaving group is weakly nucleophilic and undergoes diffusional
separation to free ions faster than addition to 1+ to form 1-(4-
C6H4OH) and 1-(2-C6H4OH) [(ko
)
idp + (ko
)idp < < k-d
ortho
≈
The rate constant k- ) 2 × 109 M-1 s-1 for addition of
para
O
1.6 × 1010 M-1 s-1 24
,
Scheme 9].
phenoxide ion to 1+ is 4-fold larger than the limiting rate
constants for encounter-limited addition of acetate and trifluo-
roethoxide ion to ring-substituted 1-phenylethyl carbocations.
We have suggested that the rate constant for formation of contact
ion pairs to oxyanions, which limits the rate of these carbocation-
nucleophile addition reactions, is roughly equal to kh for
cleavage of a hydrogen bond between the nucleophile and
solvent that frees an electron pair at oxygen to react with R+
(Scheme 8A).24,58,59 However, this model cannot account for
the relative reactivity of acetate, phenoxide and trifluoroethoxide
ions (Table 5). The strength of hydrogen bonds to anions is
proportional to anion basicity,60,61 and if hydrogen bond strength
alone controlled the rate constants for these encounter-limited
reactions the largest rate constant would be observed for addition
of acetate ion, which forms the weakest hydrogen bond to
solvent, instead of for the more basic phenoxide ion.
The observed rate constants for solvolysis of 1-OPh level
off at a constant value at high pH (Table 2), because of a change
in the preferred pathway for the cleavage of 1-OPh from an
acid-catalyzed to an uncatalyzed reaction. There is a corre-
sponding change in the yields of the solvolysis reaction products
(Table 2), because the phenoxide ion leaving group for the
uncatalyzed (spontaneous) reaction is strongly nucleophilic. The
ca. 50% yield of 1-(4-C6H4OH) and 1-(2-C6H4OH) from
spontaneous solvolysis of 1-OPh shows that the net rate constant
for collapse of the carbocation-anion pair (ip) to carbon ad-
ducts is comparable to that for irreversible separation to free
ions [(k-para
)
ip
+ (k-ortho
)
ip
≈ k-d, Scheme 9]. This is the same
requirement as for observation of a diffusion-limited reaction
between free phenoxide ion and 1+, and provides independent
evidence that the formation of this complex by encounter of
free ions is nearly irreversible.
The larger rate constant for encounter-limited addition of
phenoxide compared to acetate ion (Table 5) provides evidence
that loss of a hydrogen-bonded water from oxygen at phenoxide
ion [desolvation] is faster than the corresponding process at the
less basic acetate ion. Since no significant desolvation of oxygen
is required for formation of the carbocation-phenoxide ion pair
that collapses to the carbon-adducts 1-(4-C6H4OH) and 1-(2-
C6H4OH), we suggest that this complex forms at essentially
Spontaneous solvolysis of 1-OPh yields an excess of the ortho
compared to para phenol adduct ([1-(2-C6H4OH)]/[1-(4-
C6H4OH)] ) 1.5, Table 2), despite the larger steric barrier to
ortho, compared to para, addition that was proposed to account
for the difference in the yields of the respective adducts from
diffusion-controlled addition of phenoxide ion to 1+ ([1-(2-
C6H4OH)]/[1-(4-C6H4OH)] ) 0.55, Table 1). The 3-fold
difference in the relative yields of 1-(2-C6H4OH) and 1-(4-
C6H4OH) from these two reactions shows that these carbon
adducts cannot form by partitioning of the same ion pair
intermediate.
(57) McClelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.; Steenken, S.
J. Am. Chem. Soc. 1991, 113, 1009-1014.
(58) Richard, J. P. J. Chem. Soc., Chem. Commun. 1987, 1768-1769.
(59) McClelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.; Steenken, S.
J. Am. Chem. Soc. 1992, 114, 1816-1823.
These data require that, if 1+•PhO- were to form as an
intermediate of both spontaneous solvolysis of 1-OPh and
(60) Stahl, N.; Jencks, W. P. J. Am. Chem. Soc. 1986, 108, 4196-4205.
(61) Hine, J. J. Am. Chem. Soc. 1972, 94, 5766-5771.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15463

A R T I C L E S
Tsuji et al.
Scheme 9
diffusional encounter between 1+ and phenoxide ion, then the
Scheme 10
ion pair must collapse to product faster than reorganization of
phenoxide ion within the solvent cage [(kp-ara
) ) g
+ (k-ortho
ip ip
kreorg ≈ 1011 s-1].62 In this case, the relatively high yield of
1-(2-C6H4OH) from spontaneous solvolysis of 1-OPh would
be due to the placement initially of a C-2 ring carbon of
phenoxide in a position to add to 1+. Alternatively, formation
of 1-(2-C6H4OH) from an appropriately oriented cation and
anion may occur at the limiting rate for a bond vibration and
without passage over a significant energy barrier, in which case
the mechanism for rearrangement of 1-OPh to 1-(2-C6H4OH)
is best described as concerted.31,45 The advantage of any
concerted reaction must be small, because 1-(2-C6H4OH) and
1-(4-C6H4OH) form at similar rates from solvolysis of 1-OPh
and the latter compound should form by a stepwise pathway.
This is because the transition state for a competing concerted
reaction, with partial bonds between the benzylic and both the
phenoxide oxygen and the C-4 carbon, should be strongly
disfavored on steric grounds.
65
into eq 9 gives Λ ) 12.3 kcal/mol for the Marcus intrinsic
barrier for addition of phenol to 1+.63,64 This is similar to an
earlier estimate of Λ ) 12.2 kcal/mol of the intrinsic barrier
for addition of water to 1+ in a solvent of 50/50 trifluoroeth-
anol/water.69
Intrinsic Reactivity of Phenol Carbon and Oxygen. The
greater reactivity of the phenol oxygen compared with carbon
toward 1+ may reflect the larger thermodynamic driving force
∆G° and/or the smaller intrinsic barriers Λ for oxygen compared
with carbon addition to this electrophile,33,63,64 where Λ is
defined as the barrier for a thermoneutral reaction that can be
calculated from the experimental rate and equilibrium constants
using eq 9.65 Such intrinsic barriers are not often reported for
organic reactions, even though they play an important role in
determining the rate constants for these reactions.33,64,66-68
It is more difficult to estimate the intrinsic barrier to carbon
alkylation of phenol, because little is known about the unstable
initial product of this reaction, the cyclohexa-3,5-dienone 3
(Scheme 10). The thermodynamic driving force for addition of
the C-2 carbon of phenol to 1+ to form 1-(2-C6H4OH) has been
estimated using the thermodynamic cycle shown in Scheme 10
where: (1) ∆G°O ) -10 kcal/mol (above). (2) ∆G°E ) -17
kcal/mol is the free energy for tautomerization of the parent
cyclohexa-3,5-dienone.70a A similar value has been assumed for
tautomerization of 3. (3) ∆G°iso < -6 kcal/mol is a lower limit
estimated from Kiso > 33 000 (Scheme 3, Results section). This
is a lower limit for Kiso because 1-OH is converted essentially
quantitatively to 1-(2-C6H4OH) and 1-(4-C6H4OH) in acidic
solutions of trifluoroethanol/water. (4) ∆G°C2 ) ∆G°O + ∆G°iso
- ∆G°E < 1 kcal/mol.
2
1.36log Keq
4Λ
1
1.36
log k )
17.44 - Λ 1 -
(9)
{
(
) }
There is little selectivity between carbon and oxygen alky-
lation of phenoxide ion by 1+, where any difference in the
Marcus intrinsic barriers for these reactions has been strongly
attenuated by the large reaction driving force. Oxygen addition
of neutral phenol to form 1-OPh is strongly favorable with KO
) kPhOH/kH ) 2.4 × 107 (Scheme 10) and ∆G°O ) -10 kcal/
mol, calculated using kH ) 0.55 M-1 s-1 and kPhOH ) 1.3 ×
107 M-1 s-1 (Table 4). Substitution of values of kPhOH and KO
The value of ∆G°C2 is an upper limit calculated using a limit
of ∆G°iso < -6 kcal/mol for the favorable isomerization of
1-OPh to 1-(2-C6H4OH). However, the true value of ∆G°iso is
(66) Marcus, R. A. J. Am. Chem. Soc. 1969, 91, 7224-7225.
(67) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301-308.
(68) Richard, J. P.; Williams, K. B.; Amyes, T. L. J. Am. Chem. Soc. 1999,
121, 8403-8404.
(69) Richard, J. P.; Amyes, T. L.; Lin, S.-S.; O’Donoghue, A. C.; Toteva, M.
M.; Tsuji, Y.; Williams, K. B. AdV. Phys. Org. Chem. 2000, 35, 67-116.
(70) (a) Capponi, M.; Gut, I. G.; Hellrung, B.; Persy, G.; Wirz, J. Can. J. Chem.
1999, 77, 605-613. (b) Bagno, A.; Lucchini, V.; Scorrano, G. Bull. Soc.
Chim. Fr. 1987, 563-572.
(62) Richard, J. P.; Tsuji, Y. J. Am. Chem. Soc. 2000, 122, 3963-3964.
(63) Marcus, R. A. J. Phys. Chem. 1968, 72, 891-899.
(64) Kresge, A. J. Chem. Soc. ReV. 1973, 2, 475-503.
(65) Guthrie, J. P. J. Am. Chem. Soc. 1991, 113, 7249-7255.
9
15464 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Barriers to C and O Alkylation of Phenol
A R T I C L E S
Scheme 11
unlikely to be much more negative than -6 kcal/mol, because
a similar value of ∆G°iso ) -5 kcal (Table 3) was calculated
using high level ab initio theory and a continuum model to
estimate the differential solvation of 1-OPh and 1-(2-C6H4OH).
We conclude that addition of phenol to 1+ to form 1-(2-
C6H4OH) is close to a thermal neutral reaction with ∆G°C2
0 kcal/mol.
≈
the transition state for carbon-addition to 1+ does have the effect
of increasing the intrinsic reaction barrier, but that this increase
is masked by transition state stabilization through the more
favorable, stabilizing, overlap of the relevant molecular orbitals
at the soft-soft C-C nucleophile-electrophile pair compared
with the corresponding orbitals at the hard-soft O-C pair.2,73
We find that there is a > 6 kcal/mol driving force for
isomerization of 1-OPh to 1-(2-C6H4OH) [∆G°iso, Scheme 10],
which is consistent with the notion that C-C bond formation
is favored thermodynamically compared with C-O bond
formation. The formation of C-C compared with C-O bonds
will be favored kinetically by a tendency of the so-called soft-
soft interaction to reduce the intrinsic reaction barrier, provided
there is a large development of this product stabilizing interac-
tion between soft nucleophiles and soft electrophiles at the
transition state for covalent bond formation.67,71,74
The Marcus intrinsic barriers for protonation of an acetone-
like enolate by water (Λ ) 14.7 kcal/mol for kHOH, Scheme
11), and for intramolecular addition of this enolate to a ben-
zaldehyde-like carbonyl group (Λ ) 14.1 kcal/mol for kC) are
also similar, despite the large difference in electronic reorga-
nization at the hard electrophile (water) and the soft electrophile
(the carbonyl group) that occurs on proceeding to the respective
reaction transition states for nucleophile addition.75 Computa-
tional studies to model the relative intrinsic barriers for the
reactions of hard (phenol oxygen) and soft (o, p-phenol carbon
and simple enolates) nucleophiles, with hard (HOH) and soft
(1+ and the carbonyl group) electrophiles could provide a more
rigorous rationalization for the qualitative correlations between
organic structure and intrinsic reaction barriers.
Substitution of KC ≈ 1 and kC2 ) 6 × 104 M-1 s-1 (Table 4)
into eq 9 gives Λ ≈ 11 kcal/mol for the Marcus intrinsic barrier
for nucleophilic addition of the C-2 carbon of phenol of 1+,
which is slightly smaller than Λ ) 12.2 kcal/mol estimated for
nucleophilic addition of the phenol oxygen to 1+. We have
proposed that oxygen addition of phenol to 1+ proceeds by a
mechanism in which proton transfer and C-O bond formation
are concerted, so that this reaction gives 1-OPh and H+ directly
(Scheme 6). If carbon addition of phenol to 1+ is by a similar
concerted reaction mechanism, then the intrinsic barriers
reported here for carbon and oxygen alkylation of phenol may
be compared directly.
The situation is more complicated if carbon addition is by a
stepwise mechanism to form the protonated cyclohexa-3,5-
dienone, because the driving force for phenol addition to 1+
will need to be adjusted for ∆G° for proton transfer from the
intermediate to water. The pKa for this acid is not known.
However, the pKa must be perturbed downward, substantially,
from the pKa of 10 for the parent phenol and upward,
substantially, from the pKa of -3.1 for the simple ketone
acetone,70b so that proton transfer to solvent should be neither
strongly endogonic or exogonic. If this is the case, then only a
small correction of the above intrinsic reaction barrier Λ ≈ 11
kcal/mol will be required. This should not affect the qualitative
conclusions that the intrinsic barrier for C-alkylation of phenol
is similar to that for O-alkylation; and, that the larger rate
constant for oxygen compared with carbon addition of phenol
to 1+ (Table 4) is therefore due primarily to the ∼10 kcal/mol
larger driving force for oxygen addition.
There are many reactions of organic cations and anions which
show dramatic increases in Marcus intrinsic barriers with
increasing stabilization of the ion by delocalization of charge
to distant atoms. This strong correlation between intrinsic
reaction barrier and ground-state stabilization by resonance
delocalization of charge provides strong evidence that there is
a large fractional loss of stabilizing resonance interaction at the
transition states for reactions of organic ions.33,67,71,72 The
observation of similar intrinsic barriers for addition of the ortho-
carbon and oxygen of phenol to 1+ flies in the face of this trend.
A larger intrinsic barrier is predicted for carbon addition on the
basis of resonance considerations alone, because a large loss in
resonance stabilization of the aromatic ring is expected to occur
on proceeding to transition state for alkylation at C-2.
Acknowledgment. We acknowledge the National Institutes
of Health Grant GM 39754 for its generous support of this work.
We are grateful to Professor Jiali Gao at the Department of
Chemistry, University of Minnesota for assistance with the
calculation of the change in energy for isomerization of 1-OPh
to 1-(2-C6H4OH) in water. The manuscript was prepared during
the term of J.P.R. as a SFI Walton Fellow at University College,
Dublin, Ireland.
Supporting Information Available: Details of procedures for
the synthesis of 1-OPh, 1-(2-C6H4OH), and 1-(4-C6H4OH).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA037328N
We propose that, as for many other reactions, the requirement
for localization of electron density at the o-phenol carbon at
(73) Pearson, R. G., Ed. Hard and Soft Acids and Bases; Dowden, Hutchinson,
and Ross: Stroudsberg, PA, 1973.
(71) Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9-16.
(72) Bernasconi, C. F. Tetrahedron 1985, 41, 3219-3234.
(74) Bernasconi, C. F. AdV. Phys. Org. Chem. 1992, 27, 119-238.
(75) Richard, J. P.; Nagorski, R. W. J. Am. Chem. Soc. 1999, 121, 4763-4770.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15465