Electron-withdrawing substituents decrease the electrophilicity of the carbonyl carbon. An investigation with the aid of 13C NMR chemical shifts, v(C=O) frequency values, charge densities, and isodesmic reactions to interprete substituent effects on reactivity

Article abstract of DOI:10.1021/jo020121c

¹³C NMR chemical shifts and v(C=O) frequencies have been measured for several series of phenyl-or acyl-substituted phenyl acetates and for acyl-substituted methyl acetates to investigate the substituent-induced changes in the electrophilic character of the carbonyl carbon. Charge density, bond order, and energy calculations have also been performed. The spectroscopic and charge density results indicate that opposite to the conventional thinking, electron-withdrawing substituents do not increase the electrophilicity of the carbonyl carbon but instead decrease it. On the other hand, reaction energies of the isodesmic reactions designed show that electron-withdrawing substituents destabilize the carbonyl derivatives investigated. So, a significant ground-state destabilization of carboxylic acid esters, and carbonyl compounds in general, due to the decreased resonance stabilization, is proposed as a novel concept to explain both the increase in their reactivity and the changes in the chemical shifts and carbonyl frequencies induced by electron-withdrawing substituents.

Full text of DOI:10.1021/jo020121c

Electr on -With d r a w in g Su bstitu en ts Decr ea se th e Electr op h ilicity
of th e Ca r bon yl Ca r bon . An In vestiga tion w ith th e Aid of 13C NMR
Ch em ica l Sh ifts, ν(CdO) F r equ en cy Va lu es, Ch a r ge Den sities, a n d
Isod esm ic Rea ction s To In ter p r ete Su bstitu en t Effects on
Rea ctivity
Helmi Neuvonen,*,† Kari Neuvonen,† Andreas Koch,‡ Erich Kleinpeter,‡ and Paavo Pasanen†
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland, and University of Potsdam,
D-14415 Potsdam, POB 691553, Germany
helmi.neuvonen@utu.fi
Received February 21, 2002
13C NMR chemical shifts and ν(CdO) frequencies have been measured for several series of phenyl-
or acyl-substituted phenyl acetates and for acyl-substituted methyl acetates to investigate the
substituent-induced changes in the electrophilic character of the carbonyl carbon. Charge density,
bond order, and energy calculations have also been performed. The spectroscopic and charge density
results indicate that opposite to the conventional thinking, electron-withdrawing substituents do
not increase the electrophilicity of the carbonyl carbon but instead decrease it. On the other hand,
reaction energies of the isodesmic reactions designed show that electron-withdrawing substituents
destabilize the carbonyl derivatives investigated. So, a significant ground-state destabilization of
carboxylic acid esters, and carbonyl compounds in general, due to the decreased resonance
stabilization, is proposed as a novel concept to explain both the increase in their reactivity and the
changes in the chemical shifts and carbonyl frequencies induced by electron-withdrawing substit-
uents.
In tr od u ction
We demonstrated good correlations with negative
slopes for the plots of log k versus δC(CdO) for several
acyl transfer reactions including, for instance, neutral
hydrolysis of phenyl dichloroacetates or alkaline hydroly-
sis of methyl benzoates.3 An increase in the electron-
withdrawing ability of the phenyl substituent of phenyl
dichloroacetates or benzoyl substituent of methyl ben-
zoates results in an upfield shift of the carbonyl carbon
resonance. The upfield chemical shift indicates an in-
crease in shielding of the carbon in question and therefore
an increase in its electron density. One could assume this
kind of change to decrease the electrophilicity of the
carbonyl carbon and to cause an increase in ∆Gq values,
because of less favorable electrostatic interactions be-
tween the nucleophile and the acyl derivative. However,
despite the upfield shift of the δC(CdO) values, electron-
withdrawing substituents increase the rate of nucleo-
philic acyl substitutions of the esters. The δC(CdO)
characters together with the ν(CdO) values for some of
the esters studied led us to suggest that the decreased
resonance stabilization of the esters contributes to the
increase in reactivity.3
The electrophilicity of the carbonyl carbon is the main
character controlling the reactivity of several important
classes of organic compounds, such as aldehydes, ketones,
or carboxylic acid derivatives. Substituents in the react-
ing molecule still strongly adjust its reactivity. For
instance, in nucleophilic acyl substitution reactions of
carboxylic acid derivatives, electron-withdrawing sub-
stituents in the leaving group or in the nonleaving acyl
group increase reaction rates, leading to positive slopes
when correlating rate coefficients with Hammett or
related substituent constants. In general, in addition of
the possible transition state stabilization, this has been
interpreted to reflect an increase in electrophilicity of the
reaction center due to the electron withdrawal by sub-
stituents.1,2 Although there is no doubt of the electrophilic
nature of the carbonyl carbon, our recent studies con-
cerning substituent effects on the reactivity and on the
13C NMR spectroscopic characters of some carboxylic acid
esters led us to suggest a different view.3
† University of Turku.
‡ University of Potsdam.
To get our conclusions concerning this important topic
on a firmer base, we have now systematically studied
especially the effect of varying the aliphatic acyl substi-
tution on the characters of the CdO group of carboxylic
acid esters, a significant class of organic carbonyl group
containing compounds. We have studied the infrared
spectra both for the solid or liquid samples and for dilute
(1) Kirby, A. J . In Comprehensive Chemical Kinetics; Bamford, C.
H., Tipper; C. F. H., Eds.; Elsevier Publishing Co.: Amsterdam, 1980;
Vol. 10, Chapter 2, p 161.
(2) Connors, K. A. Structure Reactivity Relationships: the Study of
Reaction Rates in Solution; VCH Publishers: New York, 1990; Chapter
7, p 311.
(3) Neuvonen, H.; Neuvonen, K. J . Chem. Soc., Perkin Trans. 2 1999,
1497.
10.1021/jo020121c CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/10/2002
J . Org. Chem. 2002, 67, 6995-7003
6995

Neuvonen et al.
TABLE 1. Ca r bon yl Ca r bon 13C NMR Ch em ica l Sh ifts
δ(CdO) (in p p m ) in CDCl3 for Su bstitu ted P h en yl
Aceta tes (3), P h en yl Dich lor oa ceta tes (2), a n d P h en yl
Tr iflu or oa ceta tes (1) RCOOAr
solutions in CH2Cl2 for phenyl-substituted phenyl tri-
fluoroacetates 1, phenyl dichloroacetates 2, and phenyl
acetates 3 as well as for acyl-substituted phenyl acetates
4 and methyl acetates 5. In addition, 13C NMR shifts for
series 1, 3, 4, and 5 and for the 2,4-dinitrophenyl
derivative of series 2 as well as for 2,4-dinitrophenyl
chloroacetate (6) were measured.
R
Ar
σa
CH3
CHCl2
CF3
4-OMeC6H4
4-MeC6H4
HC6H4
4-BrC6H4
4-ClC6H4
-0.27
-0.17
0
0.23
0.23
0.37
0.66
0.71
0.78
169.87
169.69
169.49
169.07
169.17
168.97
168.46
168.70
168.38
167.60
163.37b
163.20b
163.02b
162.70b
162.78b
162.65b
162.20b
162.43b
162.13b
161.36
156.17
156.02
155.85
155.52
155.61
155.47
155.06
155.32
154.99
154.42
3-ClC6H4
4-CNC6H4
3-NO2C6H4
4-NO2C6H4
2,4-(NO2)2C6H3
a
b
Reference 6. Reference 3.
nances of the carbonyl and R-carbons in both series 4 and
5 is also evident. For 2,4-dinitrophenyl chloroacetate (6),
the 13C NMR chemical shift value of 164.58 ppm (not
shown in tables) was detected.
Carbonyl stretching frequencies of series 1-5 both for
the solid or liquid film samples and for the 0.1 M
solutions in CH2Cl2 are given in Tables S1-S4 (Support-
ing Information). Although ν(CdO) appears as a singlet
in all of the solid or liquid IR spectra, with the only
exception of 4-nitrophenyl dichloroacetate, and for all of
the CH2Cl2 solutions of phenyl-substituted phenyl tri-
fluoroacetates (1), a doublet is observed in some solution
spectra. We previously introduced two possible explana-
tions, a conformational equilibrium and Fermi resonance,
for the appearance of the doublet in the liquid film IR
spectra of 4-nitrophenyl dichloroacetate.3
Effect of th e Lea vin g Gr ou p Su bstitu en ts on th e
Electr on ic P r op er ties of th e CdO Gr ou p . 13C NMR
spectroscopy is a useful tool to study substituent effects
on the electronic environment of a carbon.5 A good
correlation but with a reverse behavior is observed
between the 13C NMR chemical shift of the CdO carbon
of monosubstituted phenyl trifluoroacetates (1) and the
Hammett σ substituent constant6 (Figure 1; Table 3, line
1). Hammett σ values describe the electronic effects of
aromatic ring substituents on the reactive center.1,2,7 The
good correlation between δC(CdO) and σ indicates that
electronic effects control the substituent-induced changes
in the CdO carbon resonance. Electron-withdrawing
substituents cause an upfield shift, indicating increased
shielding at the CdO carbon.
The relation between the spectroscopic data and the
electron densities at particular atoms as well as some
bond orders calculated by the PM3 method are discussed.
Further, the calculated heat of formation values were
used to evaluate the effect of substituents on the stabili-
ties of the esters with the aid of relevant isodesmic
reactions.
Bromilow et al.8 have previously reported a reverse
behavior of the carbonyl carbon 13C NMR shift for para-
and meta-substituted phenyl acetates. The slope of 0.96
( 0.01 (r2 ) 0.9990) between our SCS values for series 3
and those reported by Bromilow et al.8 for the common
substitutions shows a good agreement.
Resu lts a n d Discu ssion
The increase in the electron-withdrawing ability of the
phenyl substituent causes a systematic upfield shift of
the CdO carbon resonance in all three series 1-3 (Table
1). The range of the CdO carbon resonance is on the
higher field the more electronegatively substituted the
acyl group is. The significant effect of the aliphatic acyl
substitution is more clearly seen in Table 2, where the
13C NMR chemical shifts for the carbonyl and R-carbons
of acyl-substituted phenyl acetates (4) and methyl ace-
tates (5) are given. The opposite behavior of the reso-
(4) Neuvonen, H. Ber. Bunsen-Ges. Phys. Chem. 1996, 100, 1231.
(5) (a) Kalinowski, H.-O.; Berger, S.; Braun, S. Carbon-13 NMR
Spectroscopy; Wiley: Chichester, 1988; Chapter 3, p 92. (b) Sohar, P.
Nuclear Magnetic Resonance Spectroscopy; CRC Press: Boca Raton,
1983; Vol. 2, Chapter 4, p 145.
(6) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(7) (a) Hammett, L. P. Physical Organic Chemistry; McGraw-Hill:
New York, 1940; Chapter 7. (b) Hammett, L. P. Physical Organic
Chemistry, 2nd ed.; McGraw-Hill: New York, 1970; Chapter 11.
(8) Bromilow, J .; Brownlee, R. T. C.; Craik, D. J .; Fiske, P. R.; Rowe,
J . E.; Sadek, M. J . Chem. Soc., Perkin Trans 2 1981, 753.
6996 J . Org. Chem., Vol. 67, No. 20, 2002

Substituent Effects on Reactivity
TABLE 2. Ca r bon yl a n d r-ca r bon 13C NMR Ch em ica l Sh ifts (in p p m ) for Su bstitu ted P h en yl Aceta tes RCOOP h (4) a n d
Meth yl Aceta tes RCOOMe (5)a
RCOOPh
RCOOMe
R
σ* b
δ(CdO)
δ(C-R)
δ(CdO)c
δ(C-R)c
δ(CdO)
δ(C-R)
CH3CH2
CH3
-0.1
0
173.05
169.49
170.00
168.78
167.53
165.86
163.02
160.55
155.85
27.78
21.14
41.45
69.79
65.49
40.89
64.21
89.61
114.61
172.51
169.14
170.04
168.95
167.73
166.35
163.41
160.35
155.14
26.86
20.81
40.11
68.87
64.57
41.29
64.95
88.92
114.35
171.57
170.69
20.70
69.79
PhCH2
MeOCH2
PhOCH2
CH2Cl
CHCl2
CCl3
0.215
0.520
0.850
1.05
1.94
2.65
2.60
167.80
165.08
162.66
158.04
40.68
64.03
89.60
CF3
114.54
a
b
In CDCl3, if not otherwise stated. Reference 10. c In DMSO-d6
TABLE 3. Sta tistica l Da ta for Differ en t Cor r ela tion s
a n d Cr oss Cor r ela tion s of th e Ca r bon yl Ca r bon or
r-Ca r bon 13C NMR Ch em ica l Sh ifts, Su bstitu en t
Con sta n ts σ or σ*, ν(CdO) Str etch in g F r equ en cies, a n d
P M3-Ca lcu la ted Ch a r ges qC(CdO) or qO(CdO) or CdO
Bon d Or d er s for P h en yl-Su bstitu ted P h en yl Aceta tes (3),
P h en yl Dich lor oa ceta tes (2), or P h en yl Tr iflu or oa ceta tes
(1) a n d for Acyl-Su bstitu ted P h en yl Aceta tes (4) or
Meth yl Aceta tes (5)a
line
type of correlation
δC(CdO)(1) vs σ
slope
s
r2
n
1
2
3
4
5
6
7
8
9
-1.03
0.86
0.77
0.08
0.02
0.01
0.02
0.01
0.01
0.01
0.01
0.01
0.4
0.03
0.08
0.08
0.06
0.02
0.2
0.03
0.04
0.01
0.01
0.03
0.03
0.5
0.9495
9
δC(CdO)(2) vs δC(CdO)(3)
δC(CdO)(1) vs δC(CdO)(3)
δC(CdO)(1) vs ν(CdO)(1)b
0.9957 10
0.9978 10
0.7235 10
0.9095
0.8294 10
0.9199
-0.08
δC(CdO)(1) vs ν(CdO)(1)b,c -0.08
9
δC(CdO)(1) vs ν(CdO)(1)d
-0.07
δC(CdO)(1) vs ν(CdO)(1)c,d -0.07
9
δC(CdO)(2) vs ν(CdO)(2)d
δC(CdO)(3) vs ν(CdO)(3)d
-0.08
-0.07
-4.0
0.8644 10
0.8142 10
F IGURE 1. A plot of the 13C NMR chemical shifts of the
carbonyl carbon of phenyl-substituted phenyl trifluoroacetates
(1) in CDCl3 versus Hammett substituent constants σ.
10 δC(CdO)(4)e vs σ*
0.9488
0.9943
0.7029
0.8090
0.8291
0.9858
0.9883
0.9646
0.9381
0.9998
0.9996
0.9983
0.9966
0.9874
0.8364
0.9857
0.9443
8
9
9
6
9
6
5
6
6
6
5
4
4
5
4
5
8
9
9
9
7
11 δC(CdO)(4) vs δC(CdO)(4)f 0.98
12 δC(CdO)(4) vs ν(CdO)(4)b
-0.32
13 δC(CdO)(4) vs ν(CdO)(4)b,g -0.35
14 δC(CdO)(4) vs ν(CdO)(4)d
-0.33
The slopes 0.86 and 0.77 are obtained, respectively, for
the correlations between the δC(CdO) of phenyl dichlo-
roacetates (2) and phenyl acetates (3) and between those
of phenyl trifluoroacetates (1) and phenyl acetates (3).
These correlations include both the monosubstituted
derivatives and the 2,4-dinitro-substituted compounds.
The correlations are good in both cases (Table 3, lines 2
and 3), and the values of the slopessboth smaller than
1 and a smaller value in the latter casesshow that the
more electron-withdrawing substituents the acyl group
owns, the less sensitive is the carbonyl carbon resonance
to the electronic influence of the phenyl substitution. The
results indicate the decreased polarization of the carbonyl
bond when electron-withdrawal by the acyl substituents
is increased.
15 δC(CdO)(4) vs ν(CdO)(4)d,g -0.40
16 δC(CdO)(5)e vs σ*
-3.5
17 δC(CdO)(5) vs ν(CdO)(5)b
18 δC(CdO)(5) vs ν(CdO)(5)d
19 δC(CdO)(5) vs δC(CdO)(4)
-0.33
-0.30
0.98
20 δC(CdO)(7)h vs δC(CdO)(4) 0.99
21 δC(CdO)(8) vs δC(CdO)(4)
22 δC(CdO)(9) vs δC(CdO)(4)
23 δ(C-R)(4)i vs δC(CdO)(4)
24 δ(C-R)(4)j vs δC(CdO)(4)
25 δ(C-R)(5)i vs δC(CdO)(5)
0.98
0.77
-7.2
-7.7
-7.3
2.4
0.5
34
26 δC(CdO)(4) vs qC(CdO)(4)k 343
27 qC(CdO)(4) vs σ* l
-0.012 0.002 0.8784
-0.010 0.001 0.9446
28 qC(CdO)(4) vs σ* m
29 qC(CdO)(4) vs qO(CdO)(4) -0.40
0.08
170
0.7923
0.7993
30 ν(CdO)(4)d vs (CdO)
bond order (4)n
757
A fair correlation with a negative slope is verified
between δC(CdO) of series 1 and the ν(CdO) of the same
compounds (Table 3, lines 5 and 7, respectively). When
the δC(CdO) values for series 2 and 3 are correlated with
the ν(CdO) frequencies of the same series using the
values for the higher frequency peaks in those cases
where the carbonyl stretching occurs as a doublet, the
correlations are only satisfactory (Table 3, lines 8 and 9,
respectively). However, the slopes of the correlations are
similar than for series 1 (-0.07 to -0.08).
31 δC(CdO)(3) vs qC(CdO)(3)o -162
28
46
0.8309
0.9640 10
9
32 ν(CdO)(1)d vs (CdO)
bond order (1)
671
a
13C NMR chemical shifts in CDCl3, if not otherwise stated.
For IR of solid or liquid film samples. c p-CN substitution ex-
b
cluded. For IR of 0.1 M solution in CH2Cl2. e The deviating CF3
d
derivative excluded. f In DMSO-d6. The deviating points R )
g
h
PhCH2, MeOCH2, PhOCH2 excluded. δC(CdO) values for 4-nitro-
i
phenyl chloroacetate and trichloroacetate from ref 3. With R )
j
CH3, CH2Cl, CHCl2, CCl3, CF3. With R ) CH3CH2, PhCH2,
MeOCH2, PhOCH2. CH3CH2 excluded. The literature10 value of
k
l
For all three series 1-3, an increase in ν(CdO) occurs
at the same time as the carbonyl carbon resonance
displaces upfield. Systematic substituent dependent
changes in carbonyl frequency indicate primarily changes
m
2.60 for σ*(CF3) is used. The value of 3.8 determined in this work
for σ*(CF3) is used. MeOCH2 and CH2Cl excluded. o For mono-
n
substituted derivatives.
J . Org. Chem, Vol. 67, No. 20, 2002 6997

Neuvonen et al.
F IGURE 2. A plot of the 13C NMR chemical shifts of the
carbonyl carbon of acyl-substituted phenyl acetates (4) in
CDCl3 versus Taft’s polar substituent constants σ*.
F IGURE 3. Plots of the 13C NMR chemical shifts of the
carbonyl carbon of acyl-substituted methyl acetates (5; O),
4-nitrophenyl acetates (7; 0), 2,4-dinitrophenyl acetates (8; 2),
and acetyl chlorides (9; 9) in CDCl3 versus the 13C NMR
chemical shifts of acyl-substituted phenyl acetates (4) in
CDCl3.
in the force constant and hence in the bond length of the
carbon oxygen bond.9 Accordingly, the increase in
ν(CdO) can be attributed to a shorter carbonyl bond and
therefore to a higher double bond character of the CdO
bond. Both the 13C NMR and IR spectroscopic data
suggest substituent-induced increase in electron density
at the carbonyl carbon along with the increasing electron-
withdrawal by the phenyl substituent.
δC(CdO) with σ* for series 4 and 5, the value of 3.8 is
obtained as a mean value for σ*(CF3). This value can be
tested in the future as a novel polar substituent constant
of the trifluoromethyl group.
The slopes for the δC(CdO) vs ν(CdO) correlations for
series 4 and 5 are ca. -0.3 (Table 3, lines 12-15, 17, and
18). Both upfield chemical shift (increased shielding of
the carbonyl carbon) and higher ν(CdO) (a shorter CdO
bond) follow the increasing polar character of the group
R. Accordingly, electron-withdrawing acyl substituents
obviously decrease the polarization of the carbonyl group.
To study the effect of the ester leaving group on the
sensitivity of the CdO carbon resonance to the acyl
substitution, we used some cross-correlations (Figure 3).
The carbonyl carbon 13C NMR shifts of methyl acetates
(5), 4-nitrophenyl acetates (7) (the values for 4-nitro-
phenyl chloroacetate and trichloroacetate are from our
previous study),3 and 2,4-dinitrophenyl acetates (8) were
plotted against those of phenyl acetates (4). In addition
of these esters, the chemical shift values of substituted
acyl chlorides (9) found in the literature12 were also
included. Correlations are excellent in all cases, and the
points for the trifluoromethyl group nicely fit the lines.
The slopes are close to 1 for all three ester series.
Although acyl substitution effectively controls the sen-
sitivity of CdO carbon resonance to phenyl substitution,
the leaving group does not seem to possess a respective
influence. This is in line with the different efficiencies of
acyl and phenyl substitutions on the carbon resonance
as such. However, acyl chlorides (9) behave differently.
The correlation is excellent also in this case, but the
sensitivity of the carbonyl carbon 13C NMR chemical shift
to the electron-withdrawing ability of acyl substituents
is diminished as compared to that of esters. The slope is
only 0.77 (Table 3, line 22). Chlorine instead of the alkoxy
or aryl oxy group as the leaving group seems to decrease
the polarization of the CdO group. Considerably higher
ν(CdO) frequencies are observed for acyl chlorides (ca.
Effect of Acyl Su bstitu tion on th e Electr on ic
P r op er ties of th e CdO Gr ou p . To study the effect of
the structure of the aliphatic acyl group on the electronic
character of the carbonyl unit, we have used different
groups R-CO- (series 4 and 5), where Taft’s polar
substituent constant σ* for R varies from -0.1 to 2.65.10
Very large shift ranges are observed for the carbonyl
carbon resonance in series 4 and 5, 17.2 and 13.5 ppm,
respectively. The correlation of δC(CdO) with σ* 10 shows
a good correlation with a negative slope both for series 4
and 5 (Table 3, lines 10 and 16, respectively). The
carbonyl carbon resonates on the higher field, indicating
increased shielding at the CdO carbon the more electron-
withdrawing the group R is (Figure 2). We are not aware
of similar systematic correlation for a wide set of aliphatic
substitution, although reverse correlation of carbonyl
carbon resonance on aromatic substitution of benzoic acid
esters has been reported.8,11 Correlation between the δC-
(CdO) values in CDCl3 with those measured in DMSO-
d6 for series 4 is excellent with a slope of close to 1 (Table
3, line 11). CF3 was not included in the original set of
the polar substituent constants10a and the σ* value of 2.60
given in the literature for CF3 is less accurate than the
other ones.10b Therefore, we conclude that the deviation
of the point for trifluoromethyl derivative (Figure 2; Table
3, lines 10 and 16) merely reflects an unsuitable value
of σ*(CF3). If extrapolation is used for the correlations of
(9) Avram, M.; Mateescu, GH. D. Infrared Spectroscopy: Applica-
tions in Organic Chemistry; Wiley: New York, 1972; Chapter 6, p 341.
(10) (a) Taft, R. W. In Steric Effects in Organic Chemistry; Newman,
M. S., Ed.; Wiley: New York, 1956; Chapter 13, p 556. (b) Kanerva, L.
T.; Euranto, E. K. J . Chem. Soc., Perkin Trans. 2 1987, 441.
(11) (a) Dell’Erba, C.; Sancassan, F.; Novi, M.; Petrillo, G.; Mugnoli,
A.; Spinelli, D.; Consiglio, G.; Gatti, P. J . Org. Chem. 1988, 53, 3564.
(b) Dell’Erba, C.; Sancassan, F.; Leandri, G.; Novi, M.; Petrillo, G.;
Mele, A. Spinelli, D.; Consiglio, G. Gazz. Chim. Ital. 1989, 119, 643.
(c) Budeˇsˇ´ınsky´, M.; Exner, O. Magn. Reson. Chem. 1989, 27, 585.
(12) Bigi, F.; Casnati, G.; Sartori, G.; Predieri, G. J . Chem. Soc.,
Perkin Trans. 2 1991, 1319.
6998 J . Org. Chem., Vol. 67, No. 20, 2002

Substituent Effects on Reactivity
where ∆E is the average excitation energy, r the mean
radius of the 2p-orbital at the atom measured, and Σq
the charge density-bond order matrix that contains the
electron density. The mean radius r is also closely related
to changes in electron density.20,21
The correlation parameters given in Table 3 (lines 26-
30) show that the results of PM3 calculations nicely
accord with the experimental results for acyl-substituted
phenyl acetates (4). The chemical shift dependence on
electron density is normal (Table 3, line 26), while the
substituent effect on the electron density is reversed
(Table 3, lines 27 and 28). That is to say, carbonyl carbon
resonates on the lower field the more positive the charge
of the carbon is, as expected, but electron-withdrawing
substituents increase the electron density of the carbon.
Further, an opposite trend is observed between the
charges of the carbonyl carbon and carbonyl oxygen
(Table 3, line 29, negative slope). This reflects systematic
substituent-dependent variation in the polarization of the
CdO unit. The charge of oxygen is about twice as
sensitive to substitution than that of carbon. This agrees
with the reported good linear correlation with positive
slope between 17O NMR chemical shift for the carbonyl
oxygen of p-substituted methyl benzoates and the σ+
parameter.22 For methyl benzoates a reverse substituent
dependence of 13C NMR chemical shift of the CdO carbon
has also been reported.8,11 An informative correlation
with a positive slope is observed between the ν(CdO)
frequency of acyl-substituted phenyl acetates 4 and the
calculated CdO bond order (Table 3, line 30). So, as
concluded in the discussion in the previous sections, the
increase in ν(CdO) can be attributed to the increased
double bond character of the carbonyl bond.
1820 cm-1) as compared with carboxylic acid esters (ca.
1750 cm-1). The difference is thought to reflect the lower
polarization of the carbonyl bond of acyl chlorides.13
Accordingly, the decreased sensitivity of the carbonyl
carbon resonance of acyl chlorides to acyl substitution
obviously reflects the same fact.
Effect of Acyl Su bstitu tion on th e 13C NMR Ch em i-
ca l Sh ift of th e r-Ca r bon . Although the carbonyl
carbon 13C NMR shift shows a reverse trend, the R-carbon
shift behaves normally (Table 2). A good linear correla-
tion with a negative slope of -7.2 for phenyl acetates (4)
and of -7.3 for methyl acetates (5) is observed between
the chemical shift values of the R-carbon and the CdO
carbon with R ) CH3, CH2Cl, CHCl2, CCl3, or CF3 (Table
3, lines 23 and 25, respectively). With the more crowded
groups (R ) CH3CH2, PhCH2, PhOCH2, or CH3OCH2),
for phenyl acetates a separate but nearly parallel line
with a slope of -7.7 is observed (Table 3, line 24). We
conclude that these cross-correlations verify that field/
inductive electronic effects are significant in determining
the 13C NMR chemical shift of both carbons.
For series 1-3, the substituent-induced changes in
spectroscopic parameters are smaller than for acyl-
substituted esters. The changes of qC(CdO) are also
smaller than for series 4. For instance, for monosubsti-
tuted phenyl trifluoroacetates (1), the range of qC(CdO)
1
is only about
/
of that for acyl-substituted phenyl
10
acetates (4). A clear systematic variation in qC(CdO) of
series 1 could not be observed. For phenyl-substituted
phenyl acetates (3), the range of qC(CdO) is 3 times as
large as for 1 and the variation of qC(CdO) along
substitution is more systematic. However, surprisingly
in that case, the correlation between δC(CdO) and qC-
(CdO) gives a negative slope (Table 3, line 31). The PM3
results show increase in the charge of the carbonyl carbon
by electron-withdrawing substituents. Consequently, the
CdO carbon resonates on the higher field the more
positive the calculated charge of the carbon is. This is
contrast to the usually observed correlations.14-19 At this
moment, we have no distinct explanation for this fact,
but we think that in the structural systems such as
substituted phenyl esters, where the polarizable CdO
unit studied is not joined directly to the substituted ring,
the PM3 method can fail. Perhaps the calculation “sees”
as the dipole in the molecule framework most clearly the
ether oxygen-carbonyl carbon bond that is directly joined
to the aromatic ring. For series 3, the charges of qC(Cd
P M3 Ch a r ges a n d Bon d Or d er s. Although the NMR
shielding is not determined only by electron density, lin-
ear correlations with positive slopes between the charge
densities and the 13C NMR chemical shifts for probe nu-
cleus in closely similar surroundings have been observed
in several systems when varying the substitution.14-19
The carbon resonates on the higher field the higher the
electron density at the carbon is. The Karplus-Pople
approximation states that the paramagnetic term of the
shielding constant, σp, which dominates the structure
sensitivity of the chemical shift, is determined by eq 1
σp ) -constant × ∆E-1
r
-3 Σq
(1)
(13) Avram, M.; Mateescu, GH. D. Infrared Spectroscopy: Applica-
tions in Organic Chemistry; Wiley: New York, 1972; Chapter 8, p 416.
(14) Hehre, W. J .; Taft, R. W.; Topsom, R. D. Prog. Phys. Org. Chem.
1976, 12, 159.
(15) Krawczyk, H.; Szatylowicz, H.; Gryff-Keller, A. Magn. Reson.
Chem.1995, 33, 349.
(16) Lin, S.-T.; Lee, C.-C.; Liang, D. W. Tetrahedron 2000, 56, 9619.
(17) Neuvonen, K.; Fu¨lo¨p, F.; Neuvonen, H.; Koch, A.; Kleinpeter,
E.; Pihlaja, K. J . Org. Chem. 2001, 66, 4132.
(18) Matsumoto, K.; Katsura, H.; Uschida, T.; Aoyama, K.; Machigu-
chi, T. Heterocycles 1997, 45, 2443.
(20) Craik, D. J .; Brownlee, R. T. C. Prog. Phys. Org. Chem. 1983,
14, 1 and references therein.
(21) Karplus, M.; Pople, J . A. J . Chem. Phys. 1963, 38, 2803.
(22) Balakrishnan, P.; Baumstark, A. L.; Boykin, D. W. Org. Magn.
Reson. 1984, 22, 753.
(19) Alvarez-Ibarra, C.; Quiroga-Feijo´o, M. L.; Toledano, E. J . Chem.
Soc, Perkin Trans. 2 1998, 679.
J . Org. Chem, Vol. 67, No. 20, 2002 6999

Neuvonen et al.
O) and qO(CdO) change to the same direction and the
range of qO(CdO) is slightly less than the range of qC-
(CdO), while the range of qO(-O-) is higher than that
for qC(CdO). Further, qO(-O-) shows a reverse trend;
i.e., electron-withdrawing substituents increase the elec-
tron density at the ether oxygen. Due to the linear
correlation of the 13C NMR chemical shift for series 1-3
with Hammett σ and the observed correlations between
the 13C NMR chemical shifts and ν(CdO), we, however,
think that the substituent-induced changes in chemical
shift reflect electronic changes at the carbonyl carbon and
that upfield shifts of the carbonyl carbon reflect an
increase in electron density.
Interestingly, for series 1 a fair correlation with a
positive slope prevails between ν(CdO) and the CdO
bond order, indicating that an increase in ν(CdO) caused
by electron-withdrawing substituents reflects an increase
in the double bond character of the carbon-oxygen bond
(Table 3, line 32). Also for series 2 and 3, both ν(CdO)
and CdO bond order increase with increasing the elec-
tron withdrawal of phenyl substituents.
Mod e of In ter a ction betw een th e Ca r bon yl Gr ou p
a n d Su bstitu en ts. Su bstitu en t Effects a n d Rea ctiv-
ity. The spectroscopic results suggest that electron-
withdrawing substituents both in the acyl group and in
the leaving group of an ester shorten the CdO bond and
increase shielding at the carbonyl carbon. The shortening
of the carbon oxygen bond can be attributed to an
increase in its double bond character. As regards the
aliphatic acyl substitution, PM3 calculations support the
experimental results, verifying both the increase in
electron density at the carbonyl carbon and the increase
in the bond order of the carbon oxygen bond by electron-
withdrawing substituents.
Reverse substituent chemical shift effects have been
previously detected for some unsaturated carbons in the
side chains of aromatic rings. The behavior has most
often been explained by the so-called π-polarization.8,20,23-25
The substituent dipole is thought to polarize each π-unit
as a localized system (10). So, the chemical shift depen-
it does not give any explanation for the substituent effects
on the reactivity of carboxylic acid esters. A clear increase
in reaction rate of nucleophilic acyl substitutions occurs,
involving as nucleophiles for instance water, the hydrox-
ide ion, ammonia, or amines, when the electron-with-
drawing ability of substituents in the acyl or leaving
group moiety of the ester increases.1-4,27-31 So, for
instance, for the neutral hydrolysis of phenyl-substituted
phenyl trifluoroacetates in 3.89 M water in acetonitrile,
eq 2
log(k/ko) ) Fσ
(2)
gives a Hammett reaction constant (F) of 2.45.27 For the
alkaline hydrolysis of phenyl-substituted phenyl acetates
in aqueous solution, a F value of 1.1 has been reported.30
For acyl-substituted esters of aliphatic acids, the polar
effects dominate, although steric effects also contribute.31
A F* value of 2.7 and S value of 1.6 were obtained by us
when the rate coefficients of alkaline hydrolysis of acyl-
substituted ethyl acetates in aqueous solution31 were
correlated by eq 3,
log(k/ko) ) F*σ* + SEs
(3)
where Es refers to steric parameters.
So, both the 13C NMR chemical shift of the ester
carbonyl carbon and the reactivity of esters toward
nucleophiles correlate with Hammett or related substitu-
ent constants. As discussed in the Introduction, good
correlations between log k and δC(CdO) with negative
slopes have been demonstrated for several acyl substitu-
tions.
Nucleophilic acyl substitution (Scheme 1) is stepwise
via a reactive intermediate, or it occurs as a concerted
process if the intermediate is very unstable but still exists
or is too unstable to exist at all.32,33 The increase in
SCHEME 1
reactivity by electron-withdrawing substituents is con-
ventionally explained by the increase in electrophilicity
(decreased electron density) of the carbonyl carbon by
electron withdrawal, as well as by stabilization of the
transition state in those cases where negative charge is
developed on going from ground state to the transition
state.1,2 If the rate-determining step of the reaction is the
leaving-group expulsion, an increase in the rate of this
step contributes because electron-withdrawing substit-
dence on electron density is thought to be normal, while
the substituent effect on the electron density is reversed.
π-Polarization mechanism was recently criticized, but
any alternative explanation was not given.26 To our
knowledge, systematic reverse behavior of carbonyl car-
bon 13C NMR chemical shift by polar aliphatic substitu-
tions for a wide range of substitutions has not been
described previously. A π-polarization mechanism can
explain the reverse trend in the CdO carbon shifts, but
(27) Neuvonen, H. J . Chem. Soc., Perkin Trans. 2 1986, 1141.
(28) Neuvonen, H. J . Chem. Soc., Perkin Trans. 2 1995, 951.
(29) Neuvonen, H. J . Chem. Soc., Perkin Trans. 2 1987, 159.
(30) Bruice, C.; Mayahi, F. J . Am. Chem. Soc. 1960, 82, 3067
(31) Euranto, E. K.; Moisio, A.-L. Suom. Kemistil. 1964, B 37, 92
(32) (a) J encks, W. P.; Gilchrist, M. J . Am. Chem. Soc. 1968, 90,
2622. (b) Satterthwait, A. C.; J encks, W. P. J . Am. Chem. Soc. 1974,
96, 7018. (c) Gresser, M. J .; J encks, W. P. J . Am. Chem. Soc. 1977, 99,
6963, 6970. (d) Palling, D. J .; J encks, W. P. J . Am. Chem. Soc. 1984,
106, 4869. (e) Song, B. D.; J encks, W. P. J . Am. Chem. Soc. 1989, 111,
8479. (f) Stefanidis, D.; Cho, S.; Dhe-Paganon, S.; J encks, W. P. J . Am.
Chem. Soc. 1993, 115, 1650.
(23) (a) Brownlee. R. T. C.; Craik, D. J . Org. Magn. Res. 1981, 15,
248. (b) Brownlee, R. T. C.; Sadek, M.; Craik, D. J . Org. Magn. Res.
1983, 21, 616. (c) Reynolds, W. F. Prog. Phys. Org. Chem. 1983, 14,
165.
(24) Hamer, G. K.; Peat, I. R.; Reynolds, W. F. Can. J . Chem. 1973,
51, 897, 915.
(25) (a) Neuvonen, K.; Fu¨lo¨p, F.; Neuvonen, H.; Pihlaja, K. J . Org.
Chem. 1994, 59, 5895. (b) Neuvonen, K.; Fu¨lo¨p, F.; Neuvonen, H.;
Simeonov, M.; Pihlaja, K. J . Phys. Org. Chem. 1997, 10, 55.
(26) Dahn, H.; Carrupt, P.-A. Magn. Reson. Chem. 1997, 35, 577.
(33) (a) Ba-Saif, S.; Luthra, A. K.; Williams, A. J . Am. Chem. Soc.
1987, 109, 6362. (b) Ba-Saif, S.; Luthra, A. K.; Williams, A. J . Am.
Chem. Soc. 1989, 111, 2647.
7000 J . Org. Chem., Vol. 67, No. 20, 2002

Substituent Effects on Reactivity
TABLE 4. Ca lcu la ted En er gies (∆EIso in k ca l m ol-1) of
th e Tw o Isod esm ic Rea ction s Sh ow n in Sch em e 3 for
RCOOP h (4)a
uents in the leaving group increase its nucleofugality.
Electron-withdrawing substituents in the acyl group, on
the other hand, decrease the relative nucleofugality of
alkoxy or aryl oxide ions relative to amine nucleo-
philes.32c,34 Alkaline ester hydrolysis is a reaction with
rate-determining attack of the nucleophile. This reaction
is strongly accelerated by electron-withdrawing acyl
substituents and moderately accelerated by electron-
withdrawing substituents in the leaving group.1,2,31 Fur-
ther, for instance, the rate of the two-step pyridinolysis
of 2,4-dinitrophenyl benzoates with rate-determining
leaving-group expulsion is increased by electron-with-
drawing benzoyl substituents, despite the unfavorable
effect of the acyl substituents on the departure of the
aryloxy group.34 In that reaction the intermediate is not
negatively charged but zwitterionic (cf. Scheme 1). Now
the present results show that the increase in reaction
rates of carboxylic acid esters is not caused by the increase
in their electrophilicity, because an increase in electron
density of the carbonyl carbon is observed by electron-
withdrawing substituents.
∆Eiso
R
σ* b
0.1
a
b
CH3CH2
CH3
-2.22
0
-1.35
0
0
PhCH2
CH3OCH2
PhOCH2
CH2Cl
CHCl2
CCl3
0.215
0.520
0.850
1.05
-0.26
-4.04
-4.88
-4.77
-7.54
-10.43
-11.55
-0.46
-2.94
-3.74
-3.65
-6.40
-8.12
-7.50
1.94
2.65
CF3
2.60/3.8c
a
A negative ∆Eiso value indicates the substituted derivative to
b
be less stable than the parent compound CH3COOPh. Reference
10, if not otherwise stated. c Determined in this work.
or leaving group destabilize the ester structure because
of the decreased resonance stabilization. To verify this
conclusion, we also performed isodesmic calculations. The
effect of the group R (relative to R ) CH3) on the stability
of RCOOPh (4) was evaluated by the pair of isodesmic
reactions shown in Scheme 3. The results presented in
The data discussed above gives strong verification for
our previous proposal.3 The substituent effects can be
considered with the aid of the resonance structures of
an ester as follows (Scheme 2). The electron-withdrawing
SCHEME 3
SCHEME 2
substituents in the acyl (R) and aryl/alkyl (R′) groups of
the ester destabilize the resonance form 12, carrying a
positive charge at the carbon, and those in R′ also
destabilize the resonance form 13. Consequently, an
increase in the contribution of the resonance form 11 and
thereby an increase in the electron density at the
carbonyl carbon and in the bond order of the CdO bond
occur. In the case of acyl substituents, not only inductive
effects but also electrostatic effects or repulsive dipole-
dipole interaction are possible as the destabilization
mechanism of structure 12. When electron-withdrawing
substituents decrease the contribution of resonance forms
12 and/or 13, the resonance stabilization of the ester
decreases and its reactivity increases. An increase in
reaction rate means a decrease in free energy of activa-
tion: ∆Gq ) G(transition state) - G(ground state).
Althoughsopposite to the conventional thinkingsit is
now shown that electron-withdrawing substituents de-
crease the electrophilicity of the carbonyl carbon, they
can increase reactivity of carboxylic acid derivatives
because of ground-state destabilization, i.e., by an in-
crease in G(ground state). This explanation does not
exclude the contribution of the changes in G(transition
state).
terms of ∆Eiso in Table 4 (derived from the heat of
formation values of the species in the isodesmic reactions)
clearly show that electron-withdrawing acyl substituents
destabilize the ester. The effect is the stronger the higher
the polar substituent constant σ* for the group R is. The
only clearly deviating result is the negative ∆Eiso for R
) CH3CH2, for which a value close to 0 is to be expected.
Corresponding results are obtained by the both isodesmic
reactions.
Similarly, to study the influence of the phenyl sub-
stituent X (relative to X ) H) on the stabilities of ester
series 1-3, the pair of isodesmic reactions shown in
Scheme 4 was used. For all three ester series unambigu-
SCHEME 4
Isod esm ic Rea ction s. With the aid of the spectro-
scopic data and atomic charge variations, we suggest
above that electron-withdrawing substituents in the acyl
ous results are obtained (Table 5). Electron-donating
substituents stabilize the ester structure relative to the
unsubstituted one, while electron-withdrawing phenyl
substituents clearly destabilize it. Deviating values are
only obtained for series 3 by the reaction with the 2,4-
dinitrophenyl derivative and with X ) 3-NO2, shown in
Scheme 4.
(34) (a) Castro, E. A.; Steinfort, G. B. J . Chem. Soc, Perkin Trans.
2 1983, 453. (b) Castro, E. A.; Santander, C. L. J . Org. Chem. 1985,
50, 3595. (c) Castro, E. A.; Valdivia, J . L. J . Org. Chem., 1986, 51,
1668. (d) Castro, E. A.; Becerra, M. C. Bol. Soc. Chil. Quim. 1988, 33,
67.
J . Org. Chem, Vol. 67, No. 20, 2002 7001

Neuvonen et al.
TABLE 5. Ca lcu la ted En er gies (∆EIso in k ca l m ol-1) of
th e Tw o Isod esm ic Rea ction s Sh ow n in Sch em e 4 for
RCOOAr (Ser ies 1, R ) CF 3; Ser ies 2, R ) CHCl2; Ser ies 3,
R ) CH3)a
mediated reaction, only 25% of the product was the
derivative of 15 and 75% that of 14, which was an
unexpected result. Ab initio calculations showed that the
basicity of the oxygen atom of acetaldehyde is higher than
that of trifluoroacetaldehyde possessing the electron-
withdrawing substituents, making the complexation with
BF3 easier in the former case. On the experimental level,
the complexations of acetophenone (16) and trifluoro-
acetophenone (17) were studied.35 The carbonyl carbon
∆Eiso
series 1
series 2
series 3
Ar
σb
a
b
a
b
a
b
4-OMeC6H4
4-MeC6H4
HC6H4
-0.27 0.15 0.80
-0.17 0.12 0.21
0.04 0.69 -0.04 0.61
0.06 0.15 0.02 0.11
0
0
0
0
0
0
0
4-BrC6H4
4-ClC6H4
3-ClC6H4
4-CNC6H4
3-NO2C6H4
4-NO2C6H4
2,4-(NO2)2C6H3
0.23 -0.75 -0.73 -0.50 -0.48 -0.30 -0.28
0.23 -0.60 -0.48 -0.41 -0.29 -0.27 -0.15
0.37 -0.73 -0.59 -0.51 -0.37 -0.35 -0.21
0.66 -1.44 -1.53 -0.92 -1.01 -0.51 -0.60
0.71 -2.42 -1.28 -1.71 -0.57 -0.93 0.21
0.78 -2.52 -3.13 -1.60 -2.21 -0.80 -1.41
-3.73 -10.15 -1.03 -7.45 0.10 -6.32
a
A negative value indicates the substituted derivative to be less
b
stable than the parent compound (Ar ) C6H5). Reference 6.
13C NMR signals 197.94 and 179.59 ppm, respectively,
were observed for the noncomplexed 16 and 17. Analo-
gously with our present results, the signal displaces
upfield by the trifluoro substitution. The authors did not
discuss this fact, but we attribute it to the decreased
electrophilicity of 17. Treatment of a 1:1 mixture of 16
and 17 with 1 equiv of BF3‚OEt2 showed that no com-
plexation of 17 with the Lewis acid occurred, while one
with 16 was observed. The carbonyl carbon of the latter
complex is deshielded, the 13C NMR signal appearing at
214.65 ppm. It is seen that a carbonyl compound bearing
an electron-withdrawing group does not form a Lewis
acid complex easily. We conclude that the latter result
is due to the decreased polarization of the carbonyl unit.
In the case of both the acyl and leaving group substitu-
tions of carboxylic acid esters, the isodesmic reaction
energies support the concept derived on the basis of the
spectroscopic and reactivity considerations. Electron-
withdrawing substituents destabilize the ester molecule.
Rela ted Com p ou n d s. Although our experimental
study concerns only esters, the results and conclusions
help to explain the behavior of other carbonyl compounds
too. Bigi et al.12 studied the complexation of acyl chlorides
with AlCl3 in CD2Cl2 and also the effect of substitution
on reactivity in AlCl3-catalyzed aromatic acylation. Dur-
ing the interaction of acyl chlorides with AlCl3 (the
carbonyl oxygen being involved in the metal coordina-
tion), the CdO bond is weakened, and the carbonyl
carbon 13C NMR chemical shifts are displaced downfield,
while the carbonyl oxygen 17O NMR chemical shifts are
displaced upfield. Moreover, there is a linear correlation
between ∆δ (∆δ ) the chemical shift difference between
the complexed and the free acyl chloride) for the 13C and
17O chemical shifts when the group R in RCOCl varies
in the order of CH3, CH2Cl, CHCl2, and CCl3. Upon
increasing the electron-withdrawing substituents in R,
a reduction in ∆δ values was observed. This reflects a
decreased degree of complexation when the electron-
withdrawal by acyl substituents increases. In the same
order, the reactivity of acyl chloride toward acylation
decreases. This can be explained as follows.3 While the
halogen substituents can enhance the reactivity because
of the decreased resonance stabilization (analogously
with esters), they decrease the reactivity by the dimin-
ished complexation due to the decreased CdO bond
polarization and consequently diminished basicity of the
carbonyl oxygen toward the Lewis acid. The latter effect
is dominating and chloro substituents decrease the
reactivity. The present work supports this interpretation.
In a quite recent paper, Asao et al.35 report that a 1:1
mixture of p-methylbenzaldehyde (14) and p-trifluoro-
methylbenzaldehyde (15) with 1 equiv of allyltributyl-
stannane give as the major product the alcohol derived
from the trifluoromethyl derivative 15, as expected,
and only trace amounts of the alcohol derived from 14
are observed. However, in the Lewis acid BF3‚OEt2-
Con clu sion s
Electron-withdrawing substituents in the leaving group
and especially those in the aliphatic acyl group of an ester
increase the electron density at the carbonyl carbon, and
at the same time the CdO bond order increases. Conse-
quently, the electrophilicity of the carbonyl carbon de-
creases. Although electron-withdrawing substituents de-
crease the electrophilicity of the carbonyl carbon, ground-
state destabilization of the reacting estersdue to the
decreased resonance stabilizationscan effectively con-
tribute to the rate increase of nucleophilic acyl substitu-
tions, because of the decrease in ∆Gq of the nucleophilic
attack. Charge density, bond order, and isodesmic reac-
tion energy calculations support the conclusions based
on the spectroscopic data. The present experimental data
concern carboxylic acid esters. However, the same idea
offers an explanation, for instance, for the observations
concerning the important Lewis acid-mediated electro-
philic reactions of acyl chlorides and aldehydes.
Exp er im en ta l Section
Ma ter ia ls. 1e,27 1g,27 1h ,27 1i,27 1j,27 2a ,4 2b,3 2c,3 2d ,3 2e,4
2f,3 2g,28 2h ,3 2i,4 3e,4 3g,29 3i,4 and 3j29 were prepared as
reported.
1a , bp 84-85 °C/10 mmHg (lit.36 bp 150-160 °C); 1b, bp
64-65 °C/10 mmHg (lit.37 bp 88.5 °C/40 mmHg); 1c, bp 37-
(35) Asao, N.; Asano, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001,
40, 3206.
(36) Sakakibara, S.; Inukai, N. Bull. Chem. Soc. J pn. 1965, 38, 1979.
(37) Moffat, A.; Hunt, H. J . Am. Chem. Soc. 1959, 81, 2082.
7002 J . Org. Chem., Vol. 67, No. 20, 2002

Substituent Effects on Reactivity
38 °C/8 mmHg (lit.36 bp 123 °C); 1d , bp 80 °C/15 mmHg (lit.36
bp 135-142 °C); and 1f, bp 114-116 °C/15 mmHg, were
prepared from trifluoroacetic anhydride and the appropriate
phenol by slightly modifying the method of Sakakibara and
Inukai.36 Toluene was used as the solvent instead of benzene
and the reaction mixture was heated on an oil bath at 80 °C
for 5-8 h.
from the appropriate acyl chlorides and phenol in diethyl ether
in the presence of pyridine.
Commercial methyl acetates 5a -f were used as received.
Sp ectr oscop ic Mea su r em en ts. The 13C NMR spectra (500
MHz) were recorded in CDCl3 or DMSO-d6 at 27 °C at a
concentration of 0.1 mol dm-3. A low sample concentration was
used to avoid any disturbances from intermolecular associa-
tions. The deuterium of the solvent was used as a lock signal.
The spectra were measured with the 1H broad-band decoupling
technique. The chemical shifts are expressed in ppm relative
to TMS used as an internal reference. The infrared spectra of
the liquid samples were recorded for capillary films and those
of solid samples for KBr disks or by a reflection method. The
infrared spectra for the CH2Cl2 solutions were recorded using
sealed cells with KBr windows. The concentration of the
solutions was 0.1 mol dm-3 and the path length was 0.1 mm.
P M3 Ca lcu la tion s. The 3D structures of the compounds
were composed by employing the program SYBYL44 and the
structures thus obtained optimized with the TRIPOS force
field. The resulting conformations were used as starting
structures for the semiempirical calculations of conformations,
heats of formation, and atomic charges. These calculations
were performed using the semiempirical quantum mechanical
method PM345 of the program MOPAC 7.0.46 All structures
were optimized without any restriction. The quantum chemical
calculations were processed on the SGI “Octane” (2 × R 12000)
computer of the University of Potsdam.
2j, mp 97-98 °C (from diethyl ether-petroleum ether, bp
o
40-60 C); 3a , mp 31-32 °C (lit.38 mp 32-33 °C); 3b, bp 98-
99 °C/15 mmHg (lit.38 bp 210-213 °C); 3d , bp 120 °C/13
mmHg; 3f, mp 54.5-55.5 °C (lit.38 mp 56.7 °C); 3h , bp 110
°C/16 mmHg (lit.38 bp 101-103 °C/15 mmHg); and 6, mp 92-
93 °C (from hexane), were prepared from acetyl chloride and
the appropriate phenol by a standard method in diethyl ether
in the presence of pyridine. 3c, bp 78-79 °C/14 mmHg (lit.39
bp 72-74 °C/11 mmHg), was prepared from acetic anhydride
and phenol by the method described by Chattaway.40
4a , bp 130-142 °C/60-67 mmHg (lit.39 bp 82-83 °C/2
mmHg), was prepared from propionic acid and phenol in the
presence of dicyclohexyl carbodiimide (DCC) in chloroform by
following the general method described by Bruice et al.41 4b,
mp 38.9-39.3 °C (from hexane) (lit.41 mp 39.5-40 °C), and
4d , mp 55.0-55.7 °C (from diisopropyl ether) (lit.41 mp 56.5-
57.5 °C), were prepared from the appropriate carboxylic acid
and phenol in diethyl ether in the presence of DCC and the
catalyst 4-N,N-(dimethylamino)pyridine according to the gen-
eral method described by Hassner and Alexanian42 for the
esterification of carboxylic acids. 4c, bp 114-116 °C/8 mmHg
(lit.39 bp 127-128 °C/13 mmHg, lit.41 bp 69-70 °C/1.1 mmHg)
was prepared according to the method described by Bruice et
al.41 4e, mp 40.0-40.5 °C (from petroleum ether, bp 40-60
°C) (lit.39 mp 40-41 °C), and 4f, bp 122-127 °C/14 mmHg (lit.43
bp 122 °C/14 mmHg), were prepared by a standard method
Su p p or tin g In for m a tion Ava ila ble: IR stretching fre-
quencies for series 1-5 (Tables S1-S4), heat of formation
values and CdO bond orders for series 1-4 (Tables S5 and
S6), and information about the σ* constant. This material is
available free of charge via the Internet at http://pubs.acs.org.
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