Gas-phase acidities of acetophenone oximes. Substituent effect and solvent effects

Article abstract of DOI:10.1246/bcsj.20090246

Gas-phase acidities (GA) of ring-substituted (E)-acetophenone oximes, XC₆H₄C(CH₃)=NOH, were determined by measuring proton-transfer equilibria using an FT-ICR mass spectrometer. The magnitude of the substituent effect on t

Full text of DOI:10.1246/bcsj.20090246

58
Bull. Chem. Soc. Jpn. Vol. 83, No. 1, 58–65 (2010)
© 2010 The Chemical Society of Japan
Gas-Phase Acidities of Acetophenone Oximes.
Substituent Effect and Solvent Effects
Md. Mizanur Rahman Badal and Masaaki Mishima*
Institute for Materials Chemistry and Engineering, Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581
Received September 15, 2009; E-mail: mishima@ms.ifoc.kyushu-u.ac.jp
Gas-phase acidities (GA) of ring-substituted (E)-acetophenone oximes, XC6H4C(CH3)=NOH, were determined by
measuring proton-transfer equilibria using an FT-ICR mass spectrometer. The magnitude of the substituent effect on the
acidity was found to be smaller than that of corresponding phenols by a factor of 0.70. The effects of strong para ³-
acceptors such as p-NO2 and p-CN are somewhat enhanced compared with those of phenols, indicating that the negative
charge on oxygen atom of the conjugate anion of the oxime is significantly delocalized into the aromatic ³-system. In
addition, it was found that there is a good linear relationship between acidities in gas phase and in DMSO with a slope of
0.26, indicating that the solvation stabilization reduces consistently the effects of substituents without any significant
specific solvent effect on a particular substituent. This is in contrast to the phenol acidities in which the effects of electron-
rich para +R substituents in DMSO and water were enhanced significantly due to the substituent solvation-assisted
resonance (SSAR) effects. These results were consistent with computational studies at the B3LYP/6-311+G(d,p) level of
theory.
Oximes have received continuous attention in various fields
Thus, it is important to elucidate the intrinsic stabilities of
oximates free from solvent effects for understanding funda-
mental properties and developing applications for various
fields. Such information can be obtained from acidities in the
gas phase.19,20 In this study, the substituent effect on the
gas-phase acidity of (E)-acetophenone oxime, XC6H4C(CH3)=
NOH, have been investigated. The gas-phase acidities were
determined based on proton-transfer equilibria using a Fourier
transform ion cyclotron resonance (FT-ICR) mass spectrometer.
Theoretical calculations were also conducted for acetophenone
oximes, phenols, and a related system, (E)-2-phenylpropen-1-
ol, of which acidities cannot be determined experimentally.
because they possess interesting biological activities and high
potential as starting materials for the synthesis of a variety of
N-containing compounds.1-7 The conjugate anions, oximates,
represent a class of nucleophilic catalysts which has proven
to be very efficient in promoting processes such as acyl,
phosphoryl, and sulfuryl transfers which are important pro-
cesses in biological reactions as well as proton transfers. In
particular, the reactivity of oximate anions has considerably
received attention in the last two decades, because the oximates
are referred to as ¡-nucleophiles which exhibit a high
nucleophilic reactivity compared to common nucleophiles of
similar basicities.8-14 Recent work suggests that the solvent
effects in addition to differential ground-state destabilization
and transition-state stabilization effects play an important role
in determining the enhanced reactivity of ¡-nucleophiles.15,16
Bordwell and co-workers measured the acidities of acetophe-
none oximes and benzaldehyde oximes in DMSO and found
that these acidities fall within a narrow range of 3.8 pKa units
for the change from p-NO2 to p-MeO.17 Contrary to this, the
large substituent effect was observed for the pKa values of
phenols, where the p-NO2 group enhances the acidity by 7.2
pKa units.18 The small substituent effect in the oxime acidity
was attributed to a remote anion center from the substituent.
They reported further that a Hammett plot of the pKa values is
Results
Gas-Phase Acidities. The free energy changes determined
by measuring the equilibrium constant of the proton-transfer
reaction between acetophenone oximes of interest and a
reference acid (AH) of known acidity21 are summarized in
Table 1.
X
X
ð1Þ
+
+
N
OH
N
N
N
OH
H3C
H3C
O-
H3C
O-
H3C
The gas-phase acidity of the unsubstituted acetophenone
¹1
oxime is found to be 53.4 and 54.5 kJ mol stronger than
formaldehyde oxime and acetaldehyde oxime, respectively.
The increased acidity is explained by an electron-withdrawing
effect of the phenyl group through inductive and resonance
effects which stabilize the conjugate anions. The acidity
¹
linear with ·p values rather than ·p values for p-NO2 and
p-CN. These results suggested that the negative charge in the
oximate anion remains primarily on oxygen atom with little or
no ³-delocalization to the benzene ring. The localized negative
charge at the oxygen atom would cause stronger interaction
with solvent than that in phenoxides. This may also be one of
the causes for small substituent effects observed for the acidity
of acetophenone oxime and benzaldehyde oxime in DMSO.
¹1
of acetophenone oxime is 15.519 or 21.520 kJ mol weaker
than phenol, being consistent with the difference in DMSO
(17.6 kJ mol¹1).17,18 The relative gas-phase acidities of aceto-
phenone oximes are summarized in Table 2 along with the
Published on the web December 23, 2009; doi:10.1246/bcsj.20090246

M. M. R. Badal et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
59
Table 1. Free Energy Changes of Proton-Transfer Equilib-
rium and Gas-Phase Acidities (GA)a)
Table 2. Relative Gas-Phase Acidities of Acetophenone
Oximes and Phenolsa)
Subst.
Reference acid
[GA]b) ¦Go c) GAselected
Acetophenone oxime
Phenol
Subst.
b)
c)
b)
p-OCH3
m-CF3C6H4NH2
CH3NO2
p-CF3C6H4NH2
CH3NO2
p-CF3C6H4NH2
CH3NO2
p-CF3C6H4NH2
p-CH3C6H4CH2CN [1443]
CH3COOH [1429]
m-CH3C6H4CH2CN [1440]
C6H5OH [1437]
m-CH3C6H4CH2CN [1440] ¹10.5
p-FC6H4CH2CN [1433] ¹3.8
m-CH3C6H4CH2CN [1440] ¹12.0
[1460]
[1463]
[1448]
[1463]
[1448]
¹4.9
¹4.0
11.0
¹8.9
6.1
1459.0
¹¦GAexp ¹¦GAcalc
¹15.3
¹¦GAexp ¹¦GAcalc
p-NMe2
p-MeO
p-Me
H
m-F
¹8.8
¹5.0
¹4.6
0.0
22.2
24.7
29.7
40.2
49.8
60.2
79.1
69.5
87.4
¹2.5
¹4.7
¹3.0
0.0
28.2
28.4
36.4
47.7
60.7
67.2
90.3
79.4
102.8
¹11.5
¹6.6
0.0
¹10.1
¹4.8
0.0
p-CH3
1454.1
1447.5
H
[1463] ¹15.0
13.2
18.4
18.9
28.5
33.7
42.7
54.0
54.5
68.8
16.2
19.5
22.2
30.8
40.4
47.6
61.5
56.8
76.4
[1448]
¹1.2
4.7
p-Cl
m-Cl
m-F
6.8
¹7.3
¹8.4
1434.3
1429.1
1428.6
1419.0
m-CF3
p-CF3
m-NO2
3,5-(CF3)2
p-CN
p-NO2
p-Cl
m-Cl
m-CF3
CH3COOH
[1429] ¹10.0
a) Units of kJ mol¹1. b) Calculated at B3LYP/6-311+G(d,p)//
B3LYP/6-311+G(d,p). c) Ref. 19.
m-FC6H4OH
o-FC6H4OH
m-FC6H4OH
o-FC6H4OH
p-CF3C6H4CH2CN
m-ClC6H5OH
[1410]
[1418]
[1410]
[1418]
[1393]
[1402]
[1393]
7.6
1.3
2.6
¹2.9
10.8
3.8
p-CF3
1413.8
1404.8
1393.5
m-NO2
3,5-(CF3)2 p-CF3C6H4CH2CN
0.6
m-CF3C6H4CH2CN [1403]
¹9.6
0.0
2.5
Chart 1. Optimized structures of p-MeO- and p-NMe2-
substituted acetophenone oximates.
p-CN
p-NO2
p-CF3C6H4CH2CN
ClCH2COOH
[1393]
[1377]
[1377]
1393.0
1379.5
m-FC6H4COOH
6.7
tion). Characteristic geometric features were found for p-NMe2-
and p-MeO-substituted acetophenone oximates. These sub-
stituents are out of the ³-plane of the benzene ring, twisted by
ca. 90° as shown in Chart 1 while they are coplanar to the
benzene ring in the corresponding neutral molecules, suggest-
ing that the ³-interaction of these para ³-donors with the
phenyl group is largely diminished in the conjugate anion. The
same results were observed for the phenol and 2-phenylpropen-
1-ol systems.
a) Units of kJ mol¹1. b) Gas-phase acidity of reference
compounds, Ref. 21. c) Free energy changes of respective
proton-transfer equilibria.
corresponding gas-phase acidities of phenols collected from the
literature.19
Computations of Gas-Phase Acidity. The geometries of
neutral acetophenone oximes and the corresponding conjugate
anions were optimized at the B3LYP/6-311+G(d,p) level
of theory. The harmonic vibrational frequencies were also
evaluated at the same level of theory to ensure that each
optimized structure was a true minimum on the potential
energy surface and to calculate thermochemical quantities.
Although the calculated acidity values of acetophenone oximes
Discussion
Substituent Effect. Figure 1 shows a plot of the relative
gas-phase acidities of acetophenone oximes against the
corresponding acidities of benzoic acids which can be
considered to be a standard ·o-type substituent effect in the
gas phase.22 One can find a good linear relationship for non-
conjugative substituents such as meta substituents with a slope
of 0.91. On the other hand, the strongly ³-electron accepting p-
NO2 and p-CN groups show significant upward deviations from
the line. Such deviations for strong para ³-acceptors suggest
that these conjugate anions are stabilized more significantly by
the ³-delocalization of the negative charge into the ³-aryl
group compared with that in the benzoate anion. In Figure 2 are
plotted the gas-phase acidities of acetophenone oximes against
the acidities of phenols where the effects of para ³-acceptors
are well-known to be enhanced by strong ³-interaction
between these substituents and the anion center.19 There exists
a fairly linear relationship with a slope of 0.70, indicating
clearly that the negative charge on oxygen atom of the oximate
anion is significantly delocalized into the aromatic ³-system in
the same manner as that in the phenoxide. Closer examination
¹1
are consistently 10-20 kJ mol lower than those observed,
there is a good linear relationship between experimental and
calculated acidities covering a wide range from p-MeO to
p-NO2. The slope is somewhat larger than unity for an ideal fit.
acetophenone oxime:
ꢀGoacidðcalcÞ ¼ 1:08ꢀGoacidðexpÞ ꢀ 1:5ðR2 ¼ 0:996Þ ð2Þ
phenol:
ꢀGoacidðcalcÞ ¼ 1:14ꢀGoacidðexpÞ þ 2:3ðR2 ¼ 0:995Þ ð3Þ
The good linearity of the correlations indicates that the
substituent effects for the calculated acidities could be used for
comparisons of substituent effects among related substrates.
The calculated acidities of acetophenone oximes and phenols
are given in Table 2. The calculated acidities of (E)-2-phenyl-
propen-1-ols are available in Table S1 (Supporting Informa-

60
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
Gas-Phase Acidities of Acetophenone Oximes
80
NMe2 and p-MeO in the conjugate anion are perpendicular to
the ³-plane of the benzene ring as shown in Chart 1. Contrary
to this, there is no increased resonance interaction of the ³-
donor substituents in the neutral phenols because the hydroxy
group is a ³-electron donor. As a result, the acidity-weakening
effect of a para ³-donor is more effective in the acidity of
acetophenone oxime compared with that in phenol.
To describe quantitatively the contribution of the resonance
effect of para ³-acceptors involved in the substituent effect of
acidity, a correlation analysis using the Yukawa-Tsuno (Y-T)
equation (eq 4)24,25 is useful.
p-NO
2
slope = 0.91
60
p-CN
3,5-(CF )
3 2
40
p-CF
m-Cl
m-NO
2
3
m-CF
3
20
0
p-Cl
m-F
o
o
ꢀ
ꢀG ¼ µð· þ r ꢀ·RꢀÞ
ð4Þ
ꢁ
H
o
¹
ꢁ
where · and ꢀ·R are the normal substituent constant and the
resonance substituent constant, respectively, and r is the
¹
p-Me
-20
resonance demand parameter representing the degree of the ³-
delocalization of the negative charge into the aryl ³-system.
Application of the Y-T equation to acidities of acetophenone
-20
0
20
o
40
60
80
−∆G acid(g), benzoic acid/kJ
¹
oximes and phenols gave µ = ¹56.7, r = 0.86 (R2 = 0.986)
Figure 1. Plot of gas-phase acidities of acetophenone
oximes against the corresponding benzoic acids.22
¹
and µ = ¹78.8, r = 0.62 (R2 = 0.992), respectively, when p-
MeO was excluded.26 Although the reliability of the present
correlation result may be insufficient because of the limited
number of substituents involved in the correlation in addition to
the lack of suitable substituent parameters in gas phase,
80
p-NO
2
slope = 0.70
60
40
20
0
p-CN
¹
the r value of 0.86 for acidities of acetophenone oximes is
meaningfully larger than that for phenol, indicating that the
contribution of resonance effect relative to the polar effect
is larger in the oximate than in the phenoxide. This is con-
sistent with a graphical analysis shown in Figure 2. A large
contribution of resonance effect in the oximate may be related
to the larger group natural charge of the benzene ring moiety
(-qph = ¹0.265) than that of ¹0.212 in the phenoxide. In
conclusion, the substituent effect on the gas-phase acidity of
acetophenone oxime is characterized by a large ³-delocaliza-
tion of the negative charge on oxygen into the ³-aromatic
system in a manner similar to that in the phenoxide. The only
significant difference in the substituent effect is a small
susceptibility for the oxime acidity compared to the phenol
acidity. That is, the intervening -C(Me)=N- moiety reduces
the transmission of the substituent effect by a factor of 0.70. A
similar attenuation factor of 0.7 was observed for the calculated
acidities of (E)-2-phenylpropen-1-ol (calculated acidity values
are given in Table S1). Figure 3 shows a plot of gas-phase
acidities between 2-phenylpropen-1-ol and phenol. The upward
deviations of strong ³-acceptors, p-NO2 and p-CN, from the
line determined by the non-conjugative substituents are
significantly larger than those in the corresponding plot for
acetophenone oximes (Figure S1), indicating the larger ³-
delocalization effect of strong ³-acceptor in the conjugate
anion of 2-phenylpropen-1-ol than acetophenone oximate. This
is also consistent with the group natural charge (-qph) of the
phenyl moiety (¹0.340) calculated at B3LYP/6-311+G(d,p)
larger than that of acetophenone oximate (¹0.265). In
conclusion, the intervening -C(Me)=N- moiety reduces the
transmission of the inductive/field effect but the transmission
of the resonance effect is not reduced. As a result of this
3,5-(CF )
3 2
p-CF
m-NO
3
2
m-CF
3
p-Cl
m-Cl
m-F
H
p-Me
p-MeO
-20
-20
0
20
40
60
80
100
o
−∆G acid(g), phenol/kJ
Figure 2. Plot of gas-phase acidities, acetophenone oximes
vs. phenols.19
of Figure 2 reveals that the p-NO2 and p-CN groups tend to
deviate slightly upward from the line determined by non-
conjugative substituents, suggesting that the degree of ³-
delocalization of a negative charge is even larger in the oximate
than in the phenoxide. Similar deviations of strong ³-acceptors
were observed for the calculated acidities in Figure S1
(Supporting Information) though the magnitude of the devia-
tions is somewhat smaller than the experimental results.
Contrary to strong para ³-acceptors, the strong para ³-donor
p-MeO shows downward deviation from the line (Figure 2).
The same trend is also observed for the calculated acidities
including p-NMe2 (Figure S1). This result may be explained as
follows. In the neutral acetophenone oximes there exists the ³-
interaction between these ³-donor substituents and the elec-
tron-withdrawing C(Me)=NOH moiety,23 while there is no
such resonance interaction in the conjugate anions. Indeed, the
optimized geometries at B3LYP/6-311+G(d,p) indicate that p-
¹
difference in the transmission of substituent effects, a larger r
value was observed for the acetophenone oximate compared to
that for the phenoxide.

M. M. R. Badal et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
61
100
30
slope = 0.6
p-NO
slope = 0.69
2
80
60
40
20
0
20
10
p-CN
p-NO
3,5-(CF )
2
3 2
p-CF
3
p-CN
p-CF
m-NO
3
2
m-CF
3
H
p-Cl
p-Cl
m-Cl
0
m-F
p-Me
H
p-Me
p-MeO
p-NMe
p-MeO
-10
2
-10
0
10
o
20
30
40
50
-20
−∆G acid (DMSO), phenol/kJ
-20
0
20
o
40
60
80
100
120
−∆G acid(calc), phenol/kJ
Figure 5. Plot of acidities in DMSO, acetophenone oximes
vs. phenols.
Figure 3. Plot of calculated acidities, 2-phenylpropen-1-ols
vs. phenols.
acidities of p-NO2 and p-CN groups are enhanced in the phenol
compared to those expected from the acidities of acetophenone
oximes. This is remarkably different from the corresponding
plot of the gas-phase acidities in Figure 2, indicating that the
deviations for p-NO2 and p-cyano in DMSO must result from
differences in solvent effect between two systems. In the
acidities of phenoxides, the enhanced effects of these strongly
conjugative para +R substituents in DMSO were considered to
be due to attractive interactions of the ³-electron-rich sub-
stituent with DMSO by which the enhanced effects were
termed the substituent solvation-assisted resonance (SSAR)
effects by Taft.19,22 Similar but larger SSAR effects were
observed for the acidities of toluenes and anilines where the ³-
delocalization of the conjugate anions is more significant than
phenoxide.22,27 Taking these results into consideration, the
magnitude of the SSAR effects seems to be related to the
negative charge on the electron-rich substituent. Indeed, the
group natural charge of the para-nitro group increases in order
of acetophenone oximate (¹0.484) < phenoxide (¹0.538) <
anilide (¹0.585) < benzyl anion (¹0.639), being consistent
with the increase in the SSAR effect.22 Accordingly, the
deviations of p-NO2 and p-CN in Figure 5 suggest the
smaller SSAR effect in the acetophenone oximate than in the
phenoxide.
It is interesting to examine the solvent effects on the acidity
of acetophenone oxime on the basis of the theoretical
calculations. In general, reaction field models of solvation
have been used for describing the properties of molecules in
solution. In Figure 6 are plotted the relative acidities in DMSO
calculated by using Tomasi’s polarized continuum model
(PCM)28 at B3LYP/6-311+G(d,p) against the corresponding
values calculated in gas phase. Excluding strong ³-acceptor p-
NO2 and strong ³-donors, p-NMe2 and p-MeO, there exists a
good linear relationship with a slope of 0.40 and 0.46 for
acetophenone oxime and phenol, respectively. The downward
deviations of p-NMe2 and p-MeO in the acetophenone oxime
are easily understood because the optimized structures of these
conjugate anions reveal that these substituents are coplanar to
20
p-NO
2
slope = 0.26
p-CN
p-CF
3
10
p-Cl
H
0
p-Me
p-MeO
-10
-20
0
20
40
60
80
o
−∆G acid (g)/kJ
Figure 4. Plot of acidities of acetophenone oximes, DMSO
vs. gas phase.
Solvent Effects.
In Figure 4 are plotted acidities of
acetophenone oximes in DMSO17 against the corresponding
values in gas phase. There exists a linear relationship with a
slope of 0.26 (R2 = 0.988) covering a wide range of substitu-
ents. This indicates that the solvation stabilization reduces
consistently the effects of substituents, leading to a suggestion
that the negative charge in the oximate is dispersed into the
solvent without any significant specific solvent effect on a
particular substituent. This is contrast to the result observed for
phenol acidities in DMSO where enhanced substituent effects
were observed for strongly conjugative para +R substituents
such as p-NO2 and p-NO groups compared with the effects of
non-conjugative substituents in addition to the reduced sub-
stituent effect in DMSO by a factor of 0.35 relative to in the gas
phase.19,22,27 Indeed, a plot of acetophenone oxime acidities
against phenol acidities in DMSO (Figure 5) shows that the

62
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
Gas-Phase Acidities of Acetophenone Oximes
60
40
20
0
p-NO2
3,5-(CF3)2
p-CN
b
40
a
p-NO2
3,5-(CF3)2
p-CN
m-CN
p-CF3
m-NO2
20
0
m-CN
m-Cl
m-NO2
p-CF3
m-CF3
m-Cl
p-Cl
p-Cl
m-CF3
H
m-F
m-F
H
p-Me
p-MeO
p-NMe2
p-Me
p-MeO
y = -0.9 + 0.40x R2 = 0.982
y = 0.01 + 0.46x R2 = 0.985
p-NMe2
-20
-20
0
20
40
60
80
-20
0
20
40
60
80
100 120
−∆Goacid(calc) in gas-phase, oxime/kJ
−∆Goacid(calc) in gas-phase, phenol/kJ
Figure 6. Comparison of calculated acidities between gas phase and DMSO (SCRF-PCM) for acetophenone oximes (a) and phenols
(b).
the benzene ring in DMSO while they are perpendicular in gas
phase as mentioned already. A smaller deviation of p-NMe2
observed for the phenol acidity may be attributed to the twisted
structure of the p-NMe2 group in the phenoxide in DMSO as
well as in gas phase. The upward deviations observed for p-
NO2 of the phenol acidity are consistent with the experimental
observation. On the other hand, the upward deviations in the
acetophenone oxime are inconsistent with the present exper-
imental results as shown in Figure 4. This suggests that though
the reaction field model of solvation using the SCRF-PCM
model describes the reduced substituent effect in DMSO the
specific solvent effects observed for the electron-rich substitu-
ents in DMSO are not described properly. Recently, Nakata
et al.29 reported theoretical calculations that the acidity-
strengthening effects of para ³-acceptors of phenols were
enhanced compared with the acidities expected from meta
substituents when these substituents were associated with
two water molecules. Theoretical calculations were therefore
conducted for the binding energies of neutral acids and the
conjugate anions with DMSO molecules at B3LYP/6-
311+G(d,p). We considered here two DMSO molecules as a
minimum solvation model. Since the oxygen atom of the polar
S=O group of DMSO is a good hydrogen-bond acceptor and
the acidic hydrogen of the CH3 group of DMSO will behave as
a hydrogen-bond donor, the first DMSO molecule binds with a
hydrogen atom of the OH group of a neutral acid or an oxygen
atom of the conjugate anion. The second DMSO molecule
would bind with an electron-rich substituent such as NO2
or CN groups. The optimized structures of the complexes
associated with two DMSO molecules are shown in Chart 2.
The binding energies of DMSO with neutral acids and the
corresponding anions are summarized in Table 3.
interaction with a DMSO molecule. Contrary to this, the ¦Ho
0,1
value of conjugate anions having an electron-withdrawing
group is smaller than the unsubstituted one and decreases with
increasing electron-withdrawing ability of the substituent. This
is also consistent with the order of the decreasing basicity of
the oxygen atom of a conjugate anion. The binding energy of
the second DMSO molecule (¦Ho1,2) with an electron-rich
substituent of the neutral acid is significantly smaller than the
first binding energy (¦Ho0,1) with the OH group. The ¦Ho
1,2
values of the acetophenone oximes are close to the ¦Ho
0,1
values of benzonitrile and nitrobenzene.30 While the ¦Ho
1,2
¹1
value for a neutral acid increases only by 2-4 kJ mol when
the substituent is changed from m-CN to p-NO2, the ¦Ho1,2 for
¹1
the conjugate anion significantly increases by 8 and 10 kJ mol
for acetophenone oximate and phenolate, respectively, indicat-
ing that conjugate anions with an electron-rich substituent are
stabilized by strong interaction with DMSO. Since the solvent
effects on the acidity should be related to the differences in
the solvation energy between a neutral and a conjugate
anion, it is interesting to consider the difference in the binding
energy (¦Ho1,2) between a neutral and a conjugate anion. The
differential binding energies (¦¦Ho1,2) given in Table 3 reveal
that the values for m-CN and m-NO2 of the acetophenone
oxime system are practically identical to the values for the
respective para derivatives, indicating the similarity in solvent
effect between meta and para substituents. Contrary to this, in
the phenol system the ¦¦Ho1,2 values for the para substituents
are clearly larger than the values for the corresponding meta
substituents. In addition, it was found that the difference
between para and meta substituents is larger for NO2 than CN,
being consistent with the order of the ³-electron-withdrawing
ability. This suggests that the resonance effects of para
substituents of phenol are enhanced by binding with DMSO.
In conclusion, the present theoretical calculations for the
binding energies of the substituent with DMSO molecule are
consistent with the concept of the SSAR effects which result
from a strong interaction of a solvent molecule and an electron-
The first binding energy (¦Ho0,1) of the OH group with a
DMSO molecule in phenols is larger than that in acetophenone
oximes, and the ¦Ho0,1 value increases when the substituent is
changed to a strong electron-withdrawing group, indicating that
the higher acidity of the OH group should have stronger

M. M. R. Badal et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
63
(a)
(b)
(c)
(d)
Chart 2. Optimized structures of complexes associated with two DMSO molecules. (a) p-Nitroacetophenone oxime, (b) p-
nitrophenol, (c) p-nitroacetophenone oximate, and (d) p-nitrophenoxide.
¹
Table 3. Stepwise Binding Energies (¦Ho) with DMSO
Calculated at B3LYP/6-311+G(d,p)a)
correlated with ·p values rather than ·p values for p-NO2 and
p-CN. Since there is a contribution of the resonance effects of
the ³-donors to stabilize the neutral acetophenone oxime as
mentioned above, the substituent effects on the acidity of
acetophenone oxime must be analyzed individually for para ³-
donors and para ³-acceptors. In fact, excluding para ³-donors,
least-squares calculation provides an excellent linear relation-
Acid
(XAH)
b)
Conjugate anion
¹
f)
¦¦Ho
1,2
(XA )
X
c)
d)
e)
¦Ho
¦Ho
¦Ho
¦Ho
0,1
1,2
0,1
1,2
Acetophenone oximes
ship of the acidities in DMSO with ·p , ¦Go(DMSO) =
¹0.1 + 13.2·p (R2 = 1.00, n = 5), indicating the significant
¹
H
m-CN
m-NO2 ¹39.9
p-CN ¹41.2
p-NO2 ¹42.4
¹36.3
¹40.7
¹65.0
¹59.0
¹52.2
¹52.6
¹48.1
¹
¹6.0
¹7.2
¹9.1
¹9.7
¹23.3
¹29.0
¹26.4
¹31.3
¹17.2
¹21.8
¹17.2
¹21.6
contribution of the resonance effect of ³-acceptors. This is
consistent with the result that the acidities in DMSO is
correlated linearly with the gas-phase acidities of which
substituent effect is described by the Y-T equation with an
¹
¹
¹
Phenols
r
of 0.84 (r = 1.00 for ·p by definition25).
H
m-CN
¹40.3
¹46.7
¹68.5
¹59.1
¹57.7
¹55.0
¹49.2
Conclusion
¹11.4
¹11.0
¹12.2
¹12.8
¹27.9
¹30.3
¹31.6
¹37.6
¹16.5
¹19.3
¹19.4
¹24.8
The substituent effect on the gas-phase acidity of acetophe-
m-NO2 ¹48.2
p-CN ¹48.2
p-NO2 ¹51.3
a) Units of kJ mol¹1. b) XAH + DMSO = XAH:DMSO.
c) XAH:DMSO + DMSO = DMSO:XAH:DMSO. d) XA +
DMSO = XA :DMSO. e) XA :DMSO + DMSO = DMSO:
XA :DMSO. f) Difference in the binding energy of the
second DMSO between anion and neutral molecule,
¦¦Ho1,2 = ¦Ho1,2(conjugate anion) ¹ ¦Ho1,2(neutral).
none oxime is characterized by a large ³-delocalization of the
negative charge on oxygen into the ³-aromatic system in
a manner similar to that in phenoxide. The intervening
-C(Me)=N- moiety reduces the transmission of the substituent
effect (inductive/field effect) by a factor of 0.70 compared with
the acidities of phenol but the transmission of the resonance
¹
¹
¹
¹
¹
effect is not reduced. As a result of this, a larger r value was
observed for the acetophenone oximate compared to that for the
phenoxide. It was found that there is a good linear relationship
between acidities in gas phase and in DMSO with a slope of
0.26, indicating that the solvation stabilization reduces con-
sistently the effects of substituents without any significant
specific solvent effect on a particular substituent. This is in
contrast to the phenol acidities in which the effects of electron-
rich para +R substituents in DMSO and water were enhanced
significantly due to the substituent solvation-assisted resonance
(SSAR) effects. These results are consistent with computational
studies at the B3LYP/6-311+G(d,p) level of theory.
rich substituent. Negligible SSAR effect observed for the
acidity of acetophenone oxime as shown in Figure 4 is also
consistent with the present calculations.
From the present results it is concluded that the substituent
effect on the acidity of acetophenone oxime is influenced
significantly by the resonance effects of para ³-acceptors in
both DMSO and gas phase. Therefore, it is necessary to re-
examine Bordwell’s observation17 that the substituent effect on
the acidity of acetophenone oxime in DMSO was linearly

64
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
Gas-Phase Acidities of Acetophenone Oximes
1.0
0.8
0.6
0.4
0.2
0.0
Experimental
Chemicals. The substituted (E)-acetophenone oximes used in
this work were prepared according to the literature.31 Acetophe-
none oxime was purchased from Tokyo Kasei Co., Tokyo.
General Procedure. A mixture of substituted acetophenone
(1 mmol) and fine powder of CaO (0.5 g, 8.9 mmol) was heated to
60-130 °C for a few minutes. Then, hydroxylamine hydrochloride
(0.208 g, 3 mmol) was added and the mixture was stirred about 2 to
12 h. Afterward, ethyl acetate (50 mL) was added to the reaction
mixture, filtered to remove CaO, then mixed with water and
extracted. The ethyl acetate solution was dried over MgSO4. The
solvent was removed in vacuo and then recrystallized from hexane
1
to give the oximes. These oximes were characterized by H NMR
(500 MHz). p-CH3OC6H4C(CH3)=NOH, mp 82-83 °C, 1H NMR
(CDCl3): ¤ 2.26 (3H, s, CH3), 3.83 (3H, s, OCH3), 6.90 (2H, d, J =
8.8 Hz, Ar), 7.58 (2H, d, J = 8.8 Hz, Ar). p-CH3C6H4C(CH3)=
0
5
10
15
time/s
Figure 7. Time profile of anions formed from the binary
mixture of m-CF3C6H4C(CH3)=NOH (1.61 © 10¹7 Torr)
and o-FC6H4OH (2.27 © 10¹7 Torr). Closed circles; m/z
111 (o-FC6H4OH), open circles; m/z 202 (m-CF3C6H4C-
(CH3)=NOH).
1
NOH, mp 88-89 °C, H NMR (CDCl3): ¤ 2.27 (3H, s, CH3), 2.37
(3H, s, Ar-CH3), 7.18 (2H, d, J = 8.3 Hz, Ar), 7.52 (2H, d, J = 8.0
Hz, Ar). m-FC6H4C(CH3)=NOH, mp 43-44 °C, 1H NMR (CDCl3):
¤ 2.28 (3H, s, CH3), 7.05-7.09 (1H, m, Ar), 7.32-7.41 (3H, m, Ar).
1
p-ClC6H4C(CH3)=NOH, mp 89-90 °C, H NMR (CDCl3): ¤ 2.26
¹
rapidly with CH3O to yield M ¹ 1 negative ions (eqs 6 and 7).
(3H, s, CH3), 7.35 (2H, d, J = 8.6 Hz, Ar), 7.57 (2H, d, J = 8.6 Hz,
Ar). m-ClC6H4C(CH3)=NOH, mp 87-88 °C, H NMR (CDCl3): ¤
1
The partial pressures of the oximes and the reference acids were
maintained at lower than 4 © 10¹7 Torr. The proton-transfer
equilibrium (eq 8) was achieved within 5-40 s of initiation of
the reaction (depending on the pressure of neutrals) as shown in
Figure 7. The equilibrium constant and free energy change for the
reaction were evaluated by using the expression (eq 9).
2.26 (3H, s, CH3), 7.30-7.36 (2H, m, Ar), 7.50-7.52 (1H, m, Ar),
7.62-7.63 (1H, m, Ar). m-CF3C6H4C(CH3)=NOH, mp 66-68 °C,
1H NMR (CDCl3): ¤ 2.28 (3H, s, CH3), 7.47-7.50 (1H, m, Ar),
7.58-7.60 (1H, m, Ar), 7.81-7.83 (1H, m, Ar), 7.94-7.95 (1H,
m, Ar). p-CF3C6H4C(CH3)=NOH, mp 107-108 °C, 1H NMR
(CDCl3): ¤ 2.30 (3H, s, CH3), 7.63 (2H, d, J = 10.5 Hz, Ar),
7.75 (2H, d, J = 10.5 Hz, Ar). m-NO2C6H4C(CH3)=NOH, mp
135-136 °C, 1H NMR (CDCl3): ¤ 2.33 (3H, s, CH3), 7.54-7.58
(1H, m, Ar), 7.99-8.00 (1H, m, Ar), 8.21-8.22 (1H, m, Ar), 8.50-
8.51 (1H, m, Ar). 3,5-(CF3)2C6H3C(CH3)=NOH, mp 88-89 °C,
1H NMR (CDCl3): ¤ 2.32 (3H, s, CH3), 7.53 (1H, s, Ar), 7.87 (1H,
s, Ar), 8.00 (1H, s, Ar). p-CNC6H4C(CH3)=NOH, mp 140-142 °C,
1H NMR (CDCl3): ¤ 2.30 (3H, s, CH3), 7.66 (2H, d, J = 10.5 Hz,
Ar), 7.77 (2H, d, J = 10.5 Hz, Ar). p-NO2C6H4C(CH3)=NOH, mp
IðAꢀÞpðAoHÞ
K ¼
IðAoꢀÞpðAHÞ
ꢀGA ¼ ꢀRT ln K
ð9Þ
¹
¹
The relative abundances of ions A and Ao were determined
by the relative intensities of ICR mass spectra signals when
equilibrium was attained. The pressures of the neutral reactants
were measured by means of a Bayard-Alpert type ionization gauge
applying appropriate correction factors to correct the gauge reading
for the different ionization cross sections of various compounds.33
Each experiment was performed at several ratios of partial
pressures and at different overall pressures. The proton-transfer
reactions were examined by ion-eject experiments. Equilibrium
1
178-179 °C, H NMR (CDCl3): ¤ 2.32 (3H, s, CH3), 7.23 (2H, d,
J = 9.1 Hz, Ar), 7.81 (2H, d, J = 9.1 Hz, Ar). All reference acids
were obtained from commercial sources. They were purified by
recrystallization or distillation prior to use. Their purities were
checked by ICR mass spectra at positive ion mode.
constants measured in this way can be used to calculate ¦Go
at 340 K (eq 9). The average uncertainty is «0.8 kJ mol in most
acid
¹1
Gas-Phase Acidity Measurement.
The gas-phase acidity
of these cases. Each value was measured with more than two
reference acids. The gas-phase acidity values for the reference
compounds were taken from the literature.21 The ionization gauge
shielded from strong magnetic field by use of a magnetic shield
foil (Fe-Ni alloy) was directly set at the main vacuum chamber to
read the precise pressure in the ICR cell, because the ionization
gauge that was originally set at the small pipe connected with the
main chamber gave a lower reading of the pressure. In addition, the
pumping speed was also reduced by use of the gate valve, which
was set between the main chamber and a turbo-molecular pump.
The blank pressure was kept at less than 10¹9 Torr.
Calculations. Conformational searches were carried out using
Spartan ’03 (Wavefunction, Inc.), and several conformers of the
lowest energy were further optimized at the RHF/3-21G* level of
theory to search the lowest energy conformer (global minimum).
Finally, the geometries were fully optimized at the B3LYP/
6-311+G** level of theory with normal convergence using the
Gaussian 03 program.34 Vibrational normal mode analyses were
measurements were performed on an Extrel FTMS 2001 Fourier
transform mass spectrometer. Most of the experimental techniques
used for the measurements of the equilibrium constants of the
reversible proton-transfer reactions are the same as procedures
reported previously.32 The following schemes describe the
sequence of reactions which occur in a typical experiment where
AH and AoH are the measured acid and the reference acid,
respectively.
CH3ONO þ eꢀ ! CH3Oꢀ þ NO
CH3Oꢀ þ AoH ! Aoꢀ þ CH3OH
CH3Oꢀ þ AH ! Aꢀ þ CH3OH
Aoꢀ þ AH ꢀ Aꢀ þ AoH
ð5Þ
ð6Þ
ð7Þ
ð8Þ
An experiment is initiated by a 5 ms pulse of a low-energy
electron beam (0.3-0.5 eV) through the ICR cell. The electrons are
captured by methyl nitrite at a partial pressure of 1.2 © 10¹7 Torr,
¹
and CH3O is produced (eq 5). The acids AH and AoH react

M. M. R. Badal et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
65
performed at the same level to ensure that each optimized structure
was a true minimum on the potential energy surface and to
calculate the thermal correction needed to obtain the Gibbs free
energies. The zero point energies used for the thermal correction
were unscaled. Acidities in DMSO were calculated using Tomasi’s
polarized continuum model (SCRF-PCM)28 with United Atom for
Hartree-Fock (UAHF) Model to build the cavity.
18 F. G. Bordwell, R. J. McCallum, W. N. Olmstead, J. Org.
Chem. 1984, 49, 1424; F. G. Bordwell, Acc. Chem. Res. 1988, 21,
456.
19 M. Fujio, R. T. McIver, Jr., R. W. Taft, J. Am. Chem. Soc.
1981, 103, 4017.
20 L. A. Angel, K. M. Ervin, J. Phys. Chem. A 2004, 108,
8346.
21 J. E. Bartmess, in Negative Ion Energetics Data, ed. by
W. G. Mallard, P. J. Linstrom, NIST Chemistry WebBook, NIST
Standard Reference Database Number 69, National Institute of
Standards and Technology, Gaithersburg MD, 2005, 20899, http://
webbook.nist.gov.
This work was supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan and by Joint Project of Chemical Synthesis Core
Research Institutes.
22 R. W. Taft, R. D. Topsom, Prog. Phys. Org. Chem. 1987,
Supporting Information
16, 1.
23 The
13
C
chemical shift of acetophenone oxime was
para
The calculated energies (H, G, S) of acetophenone oximes, the
corresponding conjugate anions, and the related species and
Cartesian coordinates for the optimized structures are available in
Supporting Information (Tables S1-S16 and Figure S1). This
material is available free of charge on the Web at: http//www.csj.jp/
journals/bcsj/.
found to be 1.00 ppm lower than benzene in CDCl3, indicating that
the C(Me)=NOH group is a ³-acceptor. The ·p of 0.10 was
reported for CH=NHOH. C. Hansch, A. Leo, R. W. Taft, Chem.
Rev. 1991, 91, 165.
24 Y. Tsuno, M. Fujio, Adv. Phys. Org. Chem. 1999, 32, 267;
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Jpn. 1972, 45, 1519; M. Fujio, M. Mishima, Y. Tsuno, Y. Yukawa,
Y. Takai, Bull. Chem. Soc. Jpn. 1975, 48, 2127.
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