Electron-Withdrawing β-Substituent, Ring-Strain, and Ortho Effects on Reactivity, Selectivity, and Stability of o-Alkoxybenzyl Carbocations

Article abstract of DOI:10.1021/acs.jpca.5b02234

o-Alkoxybenzyl carbocations 1 and 2 were generated by laser flash photolysis of the corresponding o-alkoxybenzyl alcohols 3 and 4 to understand how the electron-withdrawing β-substituent, the ring-strain, and the ortho effects affect the reactivity (electrophilicity), selectivity, and stability of 1 and 2, and to fit the electrophilicity of 1 and 2 into the current carbocation electrophilicity scale (E). Our finding is that both the electron-withdrawing β-substituent and the ring-strain effects make 1 less stable than 2 by 3.0 kcal/mol. These effects plus the ortho effect of 2 make 1 more reactive than 2, but the selectivity of 1 and 2 toward amine nucleophiles is almost the same within experimental errors. The electrophilicity of 1 and 2 has been fit into the current carbocation electrophilicity scale (E) quite well. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.jpca.5b02234

Article
pubs.acs.org/JPCA
Electron-Withdrawing β‑Substituent, Ring-Strain, and Ortho Effects
on Reactivity, Selectivity, and Stability of o‑Alkoxybenzyl
Carbocations
Meng-Yun Tseng, Hsin-Yi Hung, and Kuangsen Sung*
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan
S
* Supporting Information
ABSTRACT: o-Alkoxybenzyl carbocations 1 and 2 were generated by
laser flash photolysis of the corresponding o-alkoxybenzyl alcohols 3
and 4 to understand how the electron-withdrawing β-substituent, the
ring-strain, and the ortho effects affect the reactivity (electrophilicity),
selectivity, and stability of 1 and 2, and to fit the electrophilicity of 1
and 2 into the current carbocation electrophilicity scale (E). Our
finding is that both the electron-withdrawing β-substituent and the
ring-strain effects make 1 less stable than 2 by 3.0 kcal/mol. These
effects plus the ortho effect of 2 make 1 more reactive than 2, but the
selectivity of 1 and 2 toward amine nucleophiles is almost the same
within experimental errors. The electrophilicity of 1 and 2 has been fit
into the current carbocation electrophilicity scale (E) quite well.
compared 1 with 2 to find out how the electron-withdrawing β-
substituent, the ring-strain effect, and the ortho effect affect the
reactivity, selectivity, and stability of 1 and 2. In addition to
that, biosynthesis of condensed tannins in vegetable might
involve the intermediates whose structures look like carboca-
tion 1,22,23 so the study on the reactivity, selectivity, and
stability of 1 and 2 might provide some information for the
biosynthesis of condensed tannins.
INTRODUCTION
■
Quinone methides, in addition to being useful synthetic
intermediates,1,2 have been proposed as intermediates in the
biosynthesis of lignin3 and in enzyme inhibition4 and play a key
role in the chemistry of antibiotic and antitumor drugs such as
mitomycin C5 and anthracyclines.6 o-Quinone methides, in
addition to being DNA alkylation agents,7,8 are found to be
intermediates from photoexcitation of vitamin K1.9,10
Methoxybenzyl carbocation is a good model for a protonated
quinone methide,11 which is a highly activated quinone
methide,12−14 and this makes its ability to alkylate DNA
much stronger.15 Therefore, alkoxybenzyl carbocations as
reactive intermediates could threaten human health and their
reactivity information should be important. Reactivity of
alkoxybenzyl carbocations toward water, alcohols, amines,
azide, and carboxylate ions has been reported.16−21
Destabilization of benzyl carbocations by electron-with-
drawing ring substituents leads to marked decreases in the
selectivity of these carbocations toward nucleophiles.16,20
However, destabilization of ring-substituted 1-phenylethyl
carbocations by an electron-withdrawing α-substituent unusu-
ally leads to a small increase in carbocation selectivity toward
nucleophiles.17,18 This unusual result was explained by the
premise that the destabilizing inductive effect of an electron-
withdrawing α-substituent is attenuated by increased resonance
delocalization of positive charge onto the phenyl ring with an
electron-donating substituent.18 We wonder if destabilization of
ring-substituted benzyl carbocations by an electron-withdraw-
ing β-substituent leads to the similar unusual results. Hence, we
designed 1 and 2, regarded 1 as a version of 2 substituted at the
β-position of the side chain with a phenoxy group, and
The systematic development of the carbocation electro-
philicity scale (E) has been well done through the kinetics of
the reactions of carbocations with anions and amines.24 Most of
carbocations whose electrophilicity (E) has been established are
Received: March 7, 2015
Revised: April 4, 2015
Published: April 8, 2015
© 2015 American Chemical Society
3905
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
highly stabilized such as tritylium and tropylium ions.
Carbocations 1 and 2 are not highly stabilized and their
electrophilicity is still unknown. Hence, this research also likes
to explore their electrophilicity and selectivity toward amine
nucleophiles, and fits their electrophilicity into the current
carbocation electrophilicity scale (E).
Scheme 1. Generation of Carbocation 1 or 2 from 3 or 4 by
Laser Flash Photolysis at λ = 266 nm or by Irradiation with
UV Light at λ = 254 nm
Ritchie25 defined and evaluated the N+ parameter in terms of
eq 1 to describe the reactivity of a wide range of amine
nucleophiles toward sp2-hybridized carbocations. In eq 1, kNu is
the second-order rate constant for the reaction of amine
nucleophiles with a carbocation, N+ is a parameter depending
on the identity of amine nucleophiles, and log k0 is a parameter
depending only on the identity of carbocations. The
comprehensive database of N+ for various amine nucleophiles
has been revised by Bunting et al.26 The constant unit slope in
eq 1 indicates that the selectivity of a carbocation toward
various amine nucleophiles is independent of the reactivity of
the carbocation. However, several nonunit slopes were found
for eq 1, and a selectivity parameter was suggested.26,27 Thus,
we used the Swain−Scott equation and replaced n and log kH O
2
254 nm for 3 h at room temperature in a photoreactor. The
substituted hydroxylamine product was purified and its H
NMR spectrum was taken.
with Bunting’s N+ and the carbocation electrophilicity (E+),
respectively (eq 2). In eq 2, correlation of the logarithm of the
second-order rate constant (log kNu) with Bunting’s N+
parameter generates the carbocation electrophilicity (E+) and
its selectivity (sE) toward amine nucleophiles. Hence, the
carbocation electrophilicity (E+) and its selectivity (sE) toward
amine nucleophiles can be evaluated in terms of eq 2.
1
Kinetic Studies for the Reactions of Carbocation 1 or
2 with Amines. Solutions for the kinetic experiments were
prepared by mixing 3 or 4, whose absorbance was adjusted to
around 0.1−0.4 at λ = 266 nm, with excess of amine
nucleophile in a 1:1 acetonitrile/water solvent, followed by
saturation with nitrogen. Laser flash photolysis of the solution
with a 266 nm single pulse from a Nd:YAG laser generated a
transient, which was monitored by following the decay of
carbocation 1 at λ = 425 nm or by following the decay of
carbocation 2 at λ = 420 nm. The temperature of all reaction
solutions was controlled at 25 °C. The observed first-order rate
constants were obtained by least-squares fitting of an
exponential function. The rate constants were obtained as the
average of 4−6 kinetic runs carried out with each solution. The
second-order rate constant kNu (M−1 s−1) for the reaction of 1
or 2 with an amine nucleophile was determined as the least-
squares estimate of the slope for the linear plot of log kobs
against the total concentration of the amine nucleophile, which
was used in the concentration range 2 × 10−2 to 1 × 10−4 M.
log kNu = N + log k0
(1)
+
log kNu = (sE)n + log k
= (sE)N + E
+ +
H2O
(2)
EXPERIMENTAL SECTION
■
Materials. The compounds of 3,4-dihydro-2H-chromen-4-
ol (3) and 1-(2-methoxyphenyl)ethanol (4) were prepared
according to the literature.28,29
Laser Flash Photolysis. The laser flash photolysis
apparatus consists of a Nd:YAG laser used at the fourth
harmonic of its fundamental wavelength (λ = 266 nm). It
delivers a maximum power ≤20 mJ/pulse at 266 nm with 6 ns
pulse width. The time-resolved monitor system, arranged in a
cross-beam configuration, consists of a 200 W Xe arc lamp, an
F/3.4 monochromator, and a photomultiplier detector. The
signals were captured by means of a digitizing oscilloscope, and
the data were processed on a computer system using suitable
software. Solutions for analysis were placed in a fluorescence
cuvette (d ≅ 10 mm). The absorbance of each solution at λ =
266 nm was adjusted to 0.1−0.4.
Generation of Carbocation 1 or 2 by Laser Flash
Photolysis. A deoxygenated 50% acetonitrile aqueous solution
of 3 or 4 was prepared with the absorbance of 0.1−0.4 at λ =
266 nm. As shown in Scheme 1, laser flash photolysis of the
solution of 3 or 4 with 266 nm single pulse from a Nd:YAG
laser generated the transient 1 or 2, which was monitored from
λ = 350 nm to λ = 520 nm to obtain the electronic absorption
of the transient.
COMPUTATIONAL DETAILS
■
All the calculations reported here were performed with the
Gaussian 03 program.30 Geometry optimization of 1, 2, 5, 6, 1-
methylallyl cation (7), and 1-butene (8) was carried out at the
B3LYP/6-31+G* level without any symmetry restriction
(Figure 1). After the geometry optimization was performed,
an analytical vibration frequency was calculated at the same
level to determine the nature of the located stationary point.
The energies of all the stationary points were calculated at the
same level with scaled zero-point vibration energies included.
The scaled factor of 0.9804 for the zero-point vibration energies
is used according to the literature.31,32
RESULTS AND DISCUSSION
■
Product Analysis for the Reaction of the Photo-
generated Carbocation 1 with NH2OH in a Photoreactor.
A 1 mL aliquot of 3 (1 mmol) in 1:1 CH3CN/H2O solution
and NH2OH (20 mmol) were placed in a quartz fluorescence
cuvette, which was then purged with nitrogen and sealed with a
Teflon cap. The solution was then irradiated with UV light at
Generation of Carbocations 1 and 2. McClelland et al.
used a xanthenol in an aqueous solution to generate a
xanthylium cation photochemically.27 Similarly, in this article,
we used the o-alkoxybenzyl alcohols 3 and 4 to prepare the o-
alkoxybenzyl carbocations 1 and 2, respectively, by laser flash
photolysis at λ = 266 nm or UV light at λ = 254 nm (Scheme
3906
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
10−5 to 2.48 × 10−4 M), and the second-order rate constant was
5.0 × 109 M−1 s−1, which reaches a diffusion-controlled reaction
and is consistent with Richard and Jencks’ experiment.16,19,20
Therefore, this transient is assigned to carbocation 1.
The transient absorption spectrum recorded after laser flash
photolysis of 3 in a deoxygenated 1:1 acetonitrile/TFE is
centered at 425 nm, which is similar to that recorded in a
deoxygenated 50% acetonitrile aqueous solution. In addition,
the electronic absorption maximum of the 2-alkoxybenzyl
cation is much more red shifted than that of the 4-alkoxybenzyl
cation. For example, the electronic absorption of the 2-
hydroxybenzyl cation is centered at 400 nm,12,33 and the
electronic absorption of the 4-hydroxybenzyl cation is centered
at 300 nm.14 The electronic absorption of the cumyl cation is
centered at 250 and 410 nm,34 whereas the electronic
absorption of the 4-methoxycumyl cation is centered at 360
nm.34 Hence, the transient from laser flash photolysis of 3 is
likely to be assigned to carbocation 1.
Methoxybenzyl alcohol radical cations can be generated by
photosensitized electron transfer33−35 or biphotonic ionization
of laser flash photolysis.38 Electronic absorption of these radical
cations is centered at 440 nm,35−37 which is close to that of the
transient we assign to carbocation 1, but the first-order decay
rate for the methoxybenzyl alcohol radical cation in water is
around 7 × 103 s−1,35 which is 2 orders of magnitude slower
than that of carbocation 1 in 50% acetonitrile aqueous solution.
In addition to that, we also correlate the single pulse energy of
laser with the absorbance of carbocation 1 at 425 nm, and the
correlation is linear (Figure 3), indicating that no biphotonic
Figure 1. Optimized structures of 1, 2, 5, and 6 at the B3LYP/6-
31+G* level.
1). Laser flash photolysis of 3 in a deoxygenated 50%
acetonitrile aqueous solution at 25 °C with 266 nm single
pulse from a Nd:YAG laser generated a transient whose
electronic absorption with maximum electronic absorption at
425 nm is shown in Figure 2. The electronic absorption of this
Figure 2. Transient absorption spectrum recorded at 160 ns after 266
nm laser excitation of 3 in a deoxygenated 50% acetonitrile aqueous
solution.
Figure 3. Correlation between the single pulse energy of laser and the
absorbance of carbocation 1 at 425 nm.
transient looks like that of o-quinone methide transient with
maximum electronic absorption at 400 nm.12,13,33 In addition,
the transient in a deoxygenated 50% acetonitrile aqueous
solution at 25 °C decays at 425 nm with good first-order
kinetics with the rate constant of 6.3 × 105 s−1 [with the rate
constant of 5.3 × 105 s−1 in 1:1 acetonitrile/trifluoroethanol
(TFE)], which is close to the rate constant for the hydration of
protonated o-quinone methide in water12 and the decay rate
constant (3.9 × 105 s−1) of 4-MeOC6H4CH+CH3 in TFE.17
When the same solution was saturated with oxygen, the
transient decayed at 425 nm with almost the same rate
constant, indicating that the transient was not quenched by
oxygen. We also did an azide trapping experiment. The solution
was treated with various concentrations of NaN3(aq) (1.55 ×
ionization occurs during laser flash photolysis.38 Hence, laser
flash photolysis of 3 in our experimental condition is unlikely to
generate the methoxybenzyl alcohol radical cation.
Laser flash photolysis of 4 in a deoxygenated 50% acetonitrile
aqueous solution at 25 °C with 266 nm single pulse from a
Nd:YAG laser generated a transient whose electronic
absorption with a broad absorption from 350 to 450 nm and
a maximum electronic absorption at 370 nm is shown in Figure
4. The electronic absorption of this transient looks like those of
o-quinone methide12,13 and xanthylium cation27 transients with
maximum electronic absorptions at 400 and 372 nm,
respectively. In addition, the transient in a deoxygenated 50%
acetonitrile aqueous solution at 25 °C decays at 420 nm with
3907
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
Table 1. Calculated Energies (hartree), Scaled Zero-Point
Energies, Scaled Energies of 1, 2, 5, 6, 7, and 8 at the
B3LYP/6-31+G* Level
compound
energy
0.9804 × ZPE
scaled energy
1
2
5
6
7
8
−423.33819
−424.54208
−424.21819
−425.41772
−156.31403
−157.22845
0.15551
0.17471
0.16659
0.18620
0.09476
0.10652
−423.18268
−424.36737
−424.05160
−425.23152
−156.21927
−157.12193
stable than 7 by 24.17 kcal/mol because the o-methoxybenzyl
substituent of 2 provides the carbocation with better
stabilization than the ally substituent does. According to eq 3
and eq 4, 1 is less stable than 2 by 3.0 kcal/mol, and this might
be attributed to two possible contributions. First, both 1 and 2
are secondary benzyl carbocations with resonance stabilization
from π-donating o-alkoxy group. The dihedral angle of O−C−
C−C+ for 1 is 9.87° and that for 2 is 0.00°, indicating that the
ring strain drives the benzyl carbocation 1 nonplanar and that
might decrease π-donating efficiency of o-alkoxy group for 1.42
Second, the major structure difference between 1 and 2 is that
the fused ring in 1 makes the secondary benzyl carbocation
susceptible to an additional through-bond inductive effect from
β-phenoxy group. Even though Kirkwood−Westheimer electro-
static theory43 (through-space) and σ-inductive theory44
(through-bond) were proposed to describe the transmission
mode of the inductive effect, both theories are very
approximate, neither is well formulated, and a better formula
is needed.44 In addition to that, bonds are also parts of the
space,44 so the conventional through-bond transmission mode
for the inductive effect should not be phased out.
Figure 4. Transient absorption spectrum recorded at 160 ns after 266
nm laser excitation of 4 in a deoxygenated 50% acetonitrile aqueous
solution.
the rate constant of 5.5 × 105 s−1 (with the rate constant of 4.7
× 105 s−1 in 1:1 acetonitrile/TFE), which is close to the rate
constant for the hydration of protonated o-quinone methide in
water12 and the decay rate constant (3.9 × 105 s−1) of 4-
MeOC6H4CH+CH3 in TFE.17 When the same solution was
saturated with oxygen, the transient decayed at 420 nm with
almost the same rate constant, indicating that the transient was
not quenched by oxygen. We also did an azide trapping
experiment. The solution was treated with various concen-
trations of NaN3(aq) (1.55 × 10−5 to 2.48 × 10−4 M), the
second-order rate constant was 5.0 × 109 M−1 s−1, which also
reaches a diffusion-controlled reaction. Therefore, this transient
is assigned to carbocation 2.
Product Analysis. In this article, we would like to find out
the reactivity and selectivity of the carbocations 1 and 2 toward
amine nucleophiles. Hence, we need to make sure that the
reactions of carbocations 1 and 2 with amine nucleophiles
would generate the corresponding substituted amine products.
Here, we demonstrate one example involving the reaction of
the photogenerated carbocation 1 with NH2OH in a
deoxygenated 1:1 H2O/CH3CN in a photoreactor with UV
light at λ = 254 nm. To mimic a pseudo-first-order reaction
condition, an excess of amine was used. After photolysis for 3 h,
1 + H2CCHCH2CH3 (8)
→ 5 + H2CCHC(+)HCH3 (7)
ΔH = 21.17 kcal/mol
(3)
2 + H2CCHCH2CH3(8)
→ 6 + H2CCHC(+)HCH3(7)
ΔH = 24.17 kcal/mol
(4)
1
the substituted hydroxylamine product was isolated and its H
NMR spectrum is consistent with the literature.39
The destabilization of the benzyl carbocation 1 by both the
through-bond inductive effect of β-phenoxy group and the ring-
strain-induced decreased π-donating stabilization of o-alkoxy
group is consistent with the kinetic studies in this article. It is
also consistent with other experimental results42 that the
second-order rate constants (kH+) for the acid-catalyzed
dehydration of 3 and 4 are 1.7 × 10−3 and 3.2 × 10−3 M−1
s−1, respectively.
Kinetic Studies for the Carbocations 1 and 2. The
observed pseudo-first-order rate constants (kobs) for the
disappearance of the carbocations 1 and 2 in the presence of
primary or secondary amines are linear in amine concentration
in a deoxygenated 50% aqueous acetonitrile. The second-order
rate constants (kNu) for nucleophilic attack of these primary
and secondary amines on the carbocations 1 and 2 were
calculated according to eq 5 and are listed in Table 2.
Stability of Carbocations 1 and 2. An isodesmic reaction
is one in which the total number of each type of bond is
identical in the reactants and products, but there may be
changes in the relationship of one bond to another.40,41
Isodesmic reactions are widely used in theoretical studies,
allowing simple calculations to give accurate estimates of
reaction heats that determine relative stability between a
substituted reactant and a substituted product.31 Compounds 1,
2, 5, 6, 1-methylallyl cation (7), and 1-butene (8) are optimized
at the level of B3LYP/6-31+G*, and their scaled energies are
shown in Table 1. The lowest-energy structures of compounds
1, 2, 5, and 6 are shown in Figure 1. Equation 3 is the isodesmic
reaction designed to determine the relative stability between 1
and 7, assuming that 1 and 5 have similar ring strains. This
reaction is endothermic with the reaction heat of 21.17 kcal/
mol, indicating that 1 is more stable than 7 by 21.17 kcal/mol.
Similarly, the isodesmic reaction of eq 4 shows that 2 is more
kobs = (kNu)[amine] + k
H2O
(5)
3908
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
Table 2. Second-Order Rate Constants (kNu, M−1 s−1) for the Reactions of Carbocations 1 and 2 with Amine Nucleophiles
H2NCH(CH2OH)(CH3)
H2NCH(CH2OH)2
H2NC(CH2OH)(CH3)2
N+
5.54
5.05
4.87
10−8kNu for 1
10−7kNu for 2
2.28 0.18
1.42 0.02
5.80 0.51
1.13 0.11
5.55 0.46
H2NNH2
8.28 1.53
H2NC(CH2OH)2(CH3)
H2NC(CH2OH)3
N+
4.36
4.15
0.29 0.02
6.44
10−8kNu for 1
10−7kNu for 2
0.59 0.09
3.07 0.59
H2NOH
4.05 0.17
1.94 0.39
15.2 0.4
HN(CH2CH2OH)(CH3)
HN(CH2CH2)2CH2
N+
5.49
7.40
7.92
10−8kNu for 1
10−7kNu for 2
1.38 0.01
5.91 0.24
4.36 0.27
37.6 1.8
10.2 0.7
45.8 3.1
HN(CH2CH2)2S
N+
10−8kNu for 1
7.27
6.89 0.39
From the second-order rate constants (kNu) in Table 2, one
can tell the relative nucleophilicity of these amines. For
example, an amine bearing an additional alkyl substituent on Cα
has a decreasing nucleophilicity, such as H2NC(CH2OH)-
(CH3)2 versus H2NCH(CH2OH)(CH3), because of increasing
steric hindrance at the α-carbon atom. Replacement of CH3
with CH2OH on Cα of an amine decreases its nucleophilicity,
such as H2 NC(CH2 OH)(CH3 )2 versus H2 NC-
(CH2OH)2(CH3) versus H2NC(CH2OH)3. Nucleophilicity of
a secondary amine is stronger than that of a primary amine,
such as HN(CH2CH2OH)(CH3) versus H2NCH(CH2OH)-
(CH3) and HN(CH2CH2)2S versus H2NCH(CH2OH)(CH3).
The relative nucleophilicity of these amines shown in Table 1
and 2 are all consistent with the literature results.26,45,46
the intercept of 5.95 as the electrophilicity (E+) of 2 and the
slope of 0.349 as the selectivity (sE) of 2 (Figure 6, eq 7). We
According to eq 2, correlation of the logarithm of the second-
order rate constants (log kNu) for nucleophilic attack of amines
on carbocation 1 with the nucleophile parameter N+ generates
the intercept of 6.27 as the electrophilicity (E+) of 1 and the
slope of 0.347 as the selectivity (sE) of 1 (Figure 5, eq 6).
Similarly, correlation of the logarithm of the second-order rate
constants (log kNu) for nucleophilic attack of amines on
carbocation 2 with the nucleophile parameter N+ produces
Figure 6. Relationship between logarithm of the second-order rate
constants (log kNu) for nucleophilic attack of amines on the
carbocation 2 and the nucleophile parameter N+ revised by Bunting
et al.26
also correlated the log kNu for ferrocenyl(p-methoxyphenyl)-
methyl cation (FAM+) obtained by Bunton et al.26,47 with N+
to produce the intercept of 1.82 as the electrophilicity (E+) of
FAM+ and the slope of 0.56 as the selectivity (sE) of FAM+ (eq
8). Correlation of the log kNu for the [p-(dimethylamino)-
phenyl]tropylium ion (TAM+) obtained by Ritchie et al.25 with
N+ produces the intercept of −0.75 as the electrophilicity (E+)
of TAM+ and the slope of 0.87 as the selectivity (sE) of TAM+
(eq 9). We also correlated the log kNu for the [p-
(dimethylamino)phenyl]tropylium ion (DMAPTr+) obtained
by Ritchie et al.26,48 with N+ to generate the intercept of −2.59
as the electrophilicity (E+) of DMAPTr + and the slope of 0.98
as the selectivity (sE) of DMAPTr+ (eq 10). Correlation of the
log kNu for 3,6-bis(dimethylamino) xanthylium cation (pyro-
nin) obtained by Ritchie et al.25,49 with N+ generates the
intercept of −3.64 as the electrophilicity (E+) of pyronin and
the slope of 1.03 as the selectivity (sE) of pyronin (eq 11). In
addition, the electrophilicity (E+) we define is correlated well
with the electrophilicity (E)50−52 for FAM+, TAM+, DMAPTr+,
Figure 5. Relationship between logarithm of the second-order rate
constants (log kNu) for nucleophilic attack of amines on the
carbocation 1 and the nucleophile parameter N+ revised by Bunting
et al.26
3909
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
Table 3. Electrophilicity (E+) of the Carbocations and Their Selectivity (sE) toward Amine Nucleophiles
1
2
FAM+
TAM+
DMAPTr+
pyronin
a
a
a,b
a,c
a
,d
a,d
E+
6.27 0.22 (3.48 )
5.95 0.12 (3.05 )
1.82 0.10 (−2.90
)
−0.75 0.50 (−4.35
)
−2.59 0.50 (−8.36
)
−3.64 0.40 (−9.67
)
sE
0.347 0.036
0.349 0.020
0.56 0.03
0.87 0.18
0.98 0.16
1.03 0.14
a
b
c
d
Carbocation electrophilicity (E) from the literature50−52 or calculation from eq 12. Reference 50. Reference 51. Reference 52.
and pyronin (eq 12). According to eq 12, the electrophilicity
(E) for 1 and 2 is calculated to be 3.48 and 3.05 (Table 3).
0.560) of the more reactive carbocations 1, 2, and FAM+. The
electrophilicity (E+) of −2.59 for DMAPTr+ is much lower
than those (6.27, 5.95, 1.82, and −0.75) of 1, 2, FAM+, and
TAM+. It is reasonable because DMAPTr+ has the p-
(dimethylamino)benzyl stabilization, which is stronger than
the p-methoxybenzyl stabilization. The selectivity (sE) of 0.980
for the less reactive DMAPTr+ is much higher than those
(0.346, 0.349, 0.560, and 0.870) of the more reactive
carbocations 1, 2, FAM+, and TAM+. The electrophilicity
(E+) of −3.64 for pyronin is much lower than those (6.27, 5.95,
1.82, −0.75, and −2.59) of 1, 2, FAM+, TAM+, and DMAPTr+.
It is reasonable because pyronin has the stabilization from two
p-(dimethylamino)benzyl and two o-phenoxy groups. The
selectivity (sE) of 1.03 for the less reactive pyronin is much
higher than those (0.346, 0.349, 0.560, 0.870, and 0.980) of the
more reactive carbocations 1, 2, FAM+, TAM+ ,and DMAPTr+.
The electrophilicity (E+) of 6.27 for 1 is slightly higher than
that (5.95) of 2. This might be attributed to three possible
contributions. First, the known ortho effect53 might reduce the
reactivity of 2 toward amine nucleophiles. Conversely, for 1, the
carbocation on the ring might make 1 easily accessible toward
amine nucleophiles through perpendicular attack. Second, as we
mention in the stability section, β-phenoxy substituent might
destabilize 1 by through-bond induction effect. Third, the ring
strain might decrease π-donating stabilization of o-alkoxy group
in 1. However, the kinetic data in this article cannot measure
the ortho effect, the through-bond induction effect, and the
ring-strain-induced decreased π-donating stabilization of o-
alkoxy group quantitatively.
log kNu(1) = (0.347 0.036)N + (6.27 0.22)
+
(r = 0.959; n = 10)
(6)
log kNu(2) = (0.349 0.020)N + (5.95 0.12)
+
(r = 0.989; n = 9)
(7)
log kNu(FAM+) = (0.56 0.03)N + (1.82 0.10)
+
(r = 0.987; n = 13)
(8)
log kNu(TAM+) = (0.87 0.18)N + (−0.75 0.50)
+
(r = 0.888; n = 13)
(9)
log kNu(DMAPTr+) = (0.98 0.16)N + (−2.59 0.50)
+
(r = 0.900; n = 12)
(10)
log kNu(pyronin) = (1.030 0.14)N + (−3.64 0.40)
+
(r = 0.942; n = 8)
(11)
E = (1.2939 0.25)E − (4.6509 0.62)
+
(r = 0.964; n = 4)
(12)
The selectivity (sE) of 0.349 for the less reactive carbocation
2 is almost the same as that (0.347) for the more reactive
carbocation 1. They are within experimental error. However,
the selectivity difference among FAM+, TAM+, DMAPTr+, and
pyronin toward amine nucleophiles is a little bit bigger. This is
because the stability difference among FAM+, TAM+,
DMAPTr+, and pyronin involves strong resonance stabilization
whereas the stability difference between the carbocations 1 and
2 involves both the long-range inductive effect and the ring-
strain-induced decreased π-donating stabilization of o-alkoxy
group.
Richard demonstrated that electron-withdrawing α-substitu-
ents that destabilize p-methoxybenzyl carbocations increase
their selectivity toward nucleophiles as measured by rate
constant ratio kH O/kTFE for partitioning between reaction with
2
H2O and trifluoroethanol: α-CH3, 1.9; α-CH2F, 2.3; α-CHF2,
2.9; α-CF3, 3.8; α-CO2Et, 2.6; α,α-CH3,CF3, 4.0; α,α-CF3,CF3,
As shown in Table 3, the electrophilicity (E+) of 1.82 for
FAM+ is much lower than those (6.27 and 5.95) of 1 and 2. It is
reasonable because FAM+ has additional ferrocenyl stabilization
in comparison with carbocations 1 and 2. The selectivity (sE) of
0.560 for the less reactive FAM+ is much higher than those
(0.346 and 0.349) for the more reactive carbocations 1 and 2.
The electrophilicity (E+) of −0.75 for TAM+ is much lower
than those (6.27, 5.95, and 1.82) of 1, 2, and FAM+. It is
reasonable because TAM+ has the stabilization from three p-
methoxybenzyl groups. The selectivity (sE) of 0.870 for the less
reactive TAM+ is much higher than those (0.346, 0.349, and
9.0.18 Similar phenomena have also been found before.17
A
possible explanation for the unusual phenomena is that α-
substituents force the positive charge of benzyl carbocations
away from the benzylic carbon to the oxygen of the p-methoxy
group.17,18 In this article, when we compare the electrophilicity
(E+) and the selectivity (sE) of 1 with those of 2, what we found
is that both the electron-withdrawing β-phenoxy substituent
and the ring-strain effects make 1 less stable than 2. These
effects plus the ortho effect of 2 make 1 more reactive than 2,
3910
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
(9) Balakrishnan, G.; Umapathy, S. Photogenerated Radical
Intermediates of Vitamin K1: A Time-Resolved Resonance Raman
Study. J. Mol. Struct. 1999, 475, 5−11.
but the selectivity of 1 and 2 toward amine nucleophiles is
almost the same within experimental errors.
(10) Gorner, H. Photoprocesses of p-Naphthoquinones and Vitamin
K1: Effects of Alcohols and Amines on the Reactivity in Solution.
Photochem. Photobiol. Sci. 2004, 3, 71−78.
CONCLUSION
■
For carbocations 1, 2, FAM+, TAM+, DMAPTr+, and pyronin,
correlation of log kNu with Bunting’s N+ parameter generates
the electrophilicity (E+) of these carbocations and their
selectivity (sE) toward various amine nucleophiles in terms of
eq 2. In addition to that, the electrophilicity of 1 and 2 has been
fit into the current carbocation electrophilicity scale (E) quite
well.
(11) McClelland, R. A.; Moriarty, M. M.; Chevalier, M. Comparison
of a Protonated Quinone Methide and a Methoxybenzyl Carbocation
Analog. J. Chem. Soc., Perkin Trans 2 2001, 2235−2236.
(12) Chiang, Y.; Kresge, A. J.; Zhu, Y. Flash Photolytic Generation of
ortho-Quinone Methide in Aqueous Solution and Study of Its
Chemistry in that Medium. J. Am. Chem. Soc. 2001, 123, 8089−8094.
(13) Chiang, Y.; Kresge, A. J.; Zhu, Y. Flash Photolytic Generation of
o-Quinone α-Phenylmethide and o-Quinone α-(p-Anisyl)methide in
Aqueous Solution and Investigation of Their Reactions in that
Medium: Saturation of Acid-Catalyzed Hydration. J. Am. Chem. Soc.
2002, 124, 717−722.
(14) Chiang, Y.; Kresge, A. J.; Zhu, Y. Flash Photolytic Generation
and Study of p-Quinone Methide in Aqueous Solution: An Estimate of
Rate and Equilibrium Constants for Heterolysis of the Carbon−
Bromine Bond in p-Hydroxybenzyl Bromide. J. Am. Chem. Soc. 2002,
124, 6349−6356.
(15) Zhou, Q.; Turnbull, K. D. Phosphodiester Alkylation with a
Quinone Methide. J. Org. Chem. 1999, 64, 2847−2851.
(16) Richard, J. P.; Amyes, T. L.; Vontor, T. Reactions of Ring-
Substituted 1-Phenyl-2,2,2-trifluoroethyl Carbocations with Nucleo-
philic Reagents: A Bridge between Carbocations Which Follow the
Reactivity-selectivity Principle and the N+ Scale. J. Am. Chem. Soc.
1992, 114, 5626−56−34.
(17) McClelland, R. A.; Cozens, F. L.; Steenken, S.; Amyes, T. L.;
Richard, J. P. Direct Observation of p-Fluoro-substituted 4-
Methoxyphenethyl Cations by Laser Flash Photolysis. J. Chem. Soc.,
Perkin Trans 2 1993, 1717−1722.
(18) Richard, J. P. Effect of Electron-withdrawing α-Substituents on
Nucleophile Selectivity toward 4-Methoxybenzyl Carbocations:
Selectivities That Are Independent of Carbocation Stability. J. Org.
Chem. 1994, 59, 25−29.
(19) Richard, J. P.; Jencks, W. P. A Simple Relationship between
Carbocation Lifetime and Reactivity-Selectivity Relationships for the
Solvolysis of Ring-substituted 1-Phenylethyl Derivatives. J. Am. Chem.
Soc. 1982, 104, 4689−4691.
(20) Richard, J. P.; Jencks, W. P. Reactions of Substituted 1-
Phenylethyl Carbocations with Alcohols and Other Nucleophilic
Reagents. J. Am. Chem. Soc. 1984, 106, 1373−1383.
In comparison with data for 2, the destabilization of 1 by
both the through-bond induction of β-phenoxy substituent and
the ring-strain-induced decreased π-donating stabilization of o-
alkoxy group is estimated around 3.0 kcal/mol. The
destabilization of 1 plus the ortho effect of 2 makes 1 more
electrophilic than 2. However, both 1 and 2 have almost the
same selectivity toward amine nucleophiles.
ASSOCIATED CONTENT
■
S
* Supporting Information
The energies and redundant internal coordinates for 1, 2, 5, 6,
7, and 8, the 1H and 13C NMR spectra of 3 and 4, as well as the
observed pseudo-first-order rate constants for the reactions of 1
and 2 with amines. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*K. Sung. E-mail: kssung@mail.ncku.edu.tw. Phone: 886-6-
2757575 ext. 65338. Fax: 886-6-2740552.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Council of Taiwan for financial
support (NSC101-2113-M-006-001-MY3) and Mr. Chia-Yung
Su for some synthetic work.
(21) Richard, J. P. Mechanisms for the Uncatalyzed and Hydrogen
Ion Catalyzed Reactions of a Simple Quinone Methide with Solvent
and Halide Ions. J. Am. Chem. Soc. 1991, 113, 4588−4595.
(22) Peter, M. G. Chemical Modifications of Biopolymers by
Quinones and Quinone Methides. Angew. Chem., Int. Ed. Engl. 1989,
28, 555−570.
(23) Roux, D. G.; Ferreira, D. The Direct Biomimetic Synthesis,
Structure and Absolute Configuration of Angular and Linear
Condensed Tannins. Prog. Chem. Org. Nat. Prod. 1982, 41, 47−76.
(24) Mayr, H.; Ofial, A. R. Electrophilicity Scales for Carbocations; In
Carbocation Chemistry; Olah, G. A., Surya Prakash, G. K., Eds.; John
Wiley & Sons, Inc.: Hoboken, NJ, USA, 2004.
(25) Ritchie, C. D. Cation-anion Combination Reactions. 26. A
Review. Can. J. Chem. 1986, 64, 2239−2250.
(26) Heo, C. K. M.; Bunting, J. W. Nucleophilicity towards a Vinylic
Carbon Atom: Rate Constants for the Addition of Amines to the 1-
Methyl-4-vinylpyridinium Cation in Aqueous Solution. J. Chem. Soc.,
Perkin Trans. 2 1994, 2279−2290.
REFERENCES
■
(1) Diao, L.; Yang, C.; Wan, P. Quinone Methide Intermediates from
the Photolysis of Hydroxybenzyl Alcohols in Aqueous Solution. J. Am.
Chem. Soc. 1995, 117, 5369−5370.
(2) Wan, P.; Barker, B.; Diao, L.; Maike, F.; Shi, Y.; Yang, C.
Quinone Methides: Relevant Intermediates in Organic Synthesis. Can.
J. Chem. 1996, 74, 465−475.
(3) Leary, G. J. Quinone Methides and the Structure of Lignin. Wood
Sci. Technol. 1980, 14, 21−34.
(4) Myers, J. K.; Cohen, J. D.; Widlanski, T. S. Substituent Effects on
Mechanism-based Inactivation of Prostatic Acid Phosphatase. J. Am.
Chem. Soc. 1995, 117, 11049−11054.
(5) Han, I.; Russell, D. J.; Kohn, H. Studies on the Mechanism of
Mitomycin C Electrophilic Transformations: Structure-reactivity
Relationships. J. Org. Chem. 1992, 57, 1799−1807.
(6) Angle, S. R.; Rainier, J. D.; Woytowicz, C. Synthesis and
Chemistry of Quinone Methide Models for the Anthracycline
Antitumor Antibiotics. J. Org. Chem. 1997, 62, 5884−5892.
(7) Pande, P.; Shearer, J.; Yang, J.; Greenberg, W. A.; Rokita, S. E.
Alkylation of Nucleic Acids by a Model Quinone Methide. J. Am.
Chem. Soc. 1999, 121, 6773−6779.
(8) Chiang, Y.; Kresge, A. J. Alkylation of Guanosine and 2′-
Deoxyguanosine by o-Quinoneα-(p-anisyl)methide in Aqueous
Solution. Org. Biomol. Chem. 2004, 2, 1090−1092.
(27) McClelland, R. A.; Banait, N.; Steenken, S. Electrophilic
Reactions of Xanthylium Carbocations Produced by Flash Photolysis
of 9-Xanthenols. J. Am. Chem. Soc. 1989, 111, 2929−2935.
(28) Barlow, J. W.; Walsh, J. J. Synthesis and Evaluation of Dimeric
1,2,3,4-Tetrahydro-naphthalenylamine and Indan-1-ylamine Deriva-
tives with Mast Cell-stabilising and Anti-allergic Activity. Eur. J. Med.
Chem. 2010, 45, 25−37.
3911
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912

The Journal of Physical Chemistry A
Article
(29) Castro, L. C. M.; Bezier, D.; Sortais, J.-B.; Darcel, C. Iron
Dihydride Complex as the Pre-catalyst for Efficient Hydrosilylation of
Aldehydes and Ketones under Visible Light Activation. Adv. Synth.
Catal. 2011, 353, 1279−1284.
(30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; et al. Gaussian 03, Revision A.1; Gaussian,
Inc.: Pittsburgh, PA, 2003.
(31) Foresman, J. B.; Frisch, A. Exploring Chemistry with Electronic
Structure Methods, 2nd ed.; Gaussian, Inc.: Pittsburgh, PA, 1996.
(32) Sung, K.; Wang, Y. Y. Mn(III)-based Oxidative Free-Radical
Cyclizations of Substituted Allyl α-Methyl-β-ketoesters: Syntheses,
DFT Calculations, and Mechanistic Studies. J. Org. Chem. 2003, 68,
2771−2778.
(33) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. Alkylation of
Amino Acids and Glutathione in Water by o-Quinone Methide:
Reactivity and Selectivity. J. Org. Chem. 2001, 66, 41−52.
(34) McClelland, R. A.; Chan, C.; Cozens, F.; Modro, A.; Steenken,
S. Laser Flash Photolysis Generation, Spectra, and Lifetimes of
Phenylcarbenium Ions in Trifluoroethanol and Hexafluoroisopropyl
Alcohol: on the UV Spectrum of the Benzyl Cation. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1337−1339.
phenyl]tropylium Ion with Nucleophiles in Water and Methanol. J.
Am. Chem. Soc. 1977, 99, 3747−3753.
(49) Ritchie, C. D.; Kubisty, C.; Ting, G. Y. Cation-Anion
Combination Reactions. 22. Rate and Equilibrium Constants for
Reactions of Pyronin and Thiopyronin with Nucleophiles. J. Am.
Chem. Soc. 1983, 105, 279−284.
(50) Mayr, H.; Kempf, B.; Ofial, A. R. π-Nucleophilicity in Carbon−
Carbon Bond-Forming Reactions. Acc. Chem. Res. 2003, 36, 66−77.
(51) Minegishi, S.; Mayr, H. How Constant Are Ritchie’s “Constant
Selectivity Relationships”? A General Reactivity Scale for n-, π-, and σ-
Nucleophiles. J. Am. Chem. Soc. 2003, 125, 286−295.
(52) Mayr, H.; Patz, M. Scales of Nucleophilicity and Electrophilicity:
A System for Ordering Polar Organic and Organometallic Reactions.
Angew. Chem., Int. Ed. Engl. 1994, 33, 938−957.
(53) Watkinson, J. G.; Watson, W.; Yates, B. L. The Effects of ortho-
Substituents on Reactivity. Part I. The Alkaline Hydrolysis of
Substituted Ethyl Phenylacetates. J. Chem. Soc. 1963, 5437−5444.
(35) Baciocchi, E.; Bietti, M.; Steenken, S. Kinetic and Product
Studies on the Side Chain Fragmentation of 1-Arylalkanol Radical
Cations in Aqueous Solution: Oxygen versus Carbon Acidity. Chem.
Eur. J. 1999, 5, 1785−1793.
(36) Baciocchi, E.; Bietti, M.; Lanzalunga, O. Mechanistic Aspects of
β-Bond-Cleavage Reactions of Aromatic Radical Cations. Acc. Chem.
Res. 2000, 33, 243−251.
(37) Branchi, B.; Bietti, M.; Ercolani, G.; Izquierdo, M. A.; Miranda,
M. A.; Stella, L. The Role of Aromatic Radical Cations and Benzylic
Cations in the 2,4,6-Triphenylpyrylium Tetrafluoroborate Photo-
sensitized Oxidation of Ring-methoxylated Benzyl Alcohols in
CH2Cl2 Solution. J. Org. Chem. 2004, 69, 8874−8885.
(38) Gadosy, T. A.; Shukla, D.; Johnston, L. J. Generation,
Characterization, and Deprotonation of Phenol Radical Cations. J.
Phys. Chem. A 1999, 103, 8834−8839.
(39) Wertz, S.; Studer, A. Metal-Free 2,2,6,6-Tetramethylpiperidin-1-
yloxy Radical (TEMPO) Catalyzed Aerobic Oxidation of Hydroxyl-
amines and Alkoxyamines to Oximes and Oxime Ethers. Helv. Chim.
Acta 2012, 95, 1758−1772.
(40) Sung, K. Substituent Effects on Stability and Isomerization
Energies of Isocyanides and Nitriles. J. Org. Chem. 1999, 64, 8984−
8989.
(41) Sung, K.; Chen, F.-L. Establishment of Steric Substituent
Constants in the Adamantane System by ab initio Calculations. Org.
Lett. 2003, 5, 889−891.
(42) Fujio, M.; Keeffe, J. R.; O’Ferrall, R. A. M.; O’Donoghue, A. C.
Unexpectedly Small ortho-Oxygen Substituent Effects on Stabilities of
Benzylic Carbocations. J. Am. Chem. Soc. 2004, 126, 9982−9992.
(43) Bowden, K.; Grubbs, E. J. Through-Bond and Through-Space
Models for Interpreting Chemical Reactivity in Organic Reactions.
Chem. Soc. Rev. 1996, 25, 171−177.
(44) Exner, O. The Inductive Effect: Theory and Quantitative
Assessment. J. Phys. Org. Chem. 1999, 12, 265−274.
(45) Bunting, J. W.; Mason, J. M.; Heo, C. K. M. Nucleophilicity
towards a Saturated Carbon Atom: Rate Constants for the Aminolysis
of Methyl 4-Nitrobenzenesulfonate in Aqueous Solution: A Compar-
ison of the n and N+ Parameters for Amine Nucleophilicity. J. Chem.
Soc., Perkin Trans. 2 1994, 2291−2300.
(46) Brotzel, F.; Chu, Y. C.; Mayr, H. Nucleophilicities of Primary
and Secondary Amines in Water. J. Org. Chem. 2007, 72, 3679−3688.
(47) Bunton, C. A.; Carrasco, N.; Davoudzadeh, F.; Watts, W. E.
Nucleophilic Addition to Ferrocenyl-stabilised Carbocations: The
Nature of the Transition State. J. Chem. Soc., Perkin Trans. 2 1980,
1520.
(48) Ritchie, C. D.; Minasz, R. J.; Kamego, A. A.; Sawada, M. Cation-
Anion Combination Reactions. 14. Reactions of [p-(Dimethylamino)-
3912
DOI: 10.1021/acs.jpca.5b02234
J. Phys. Chem. A 2015, 119, 3905−3912