Chlorination of 2-phenoxypropanoic acid with NCP in aqueous acetic acid: Using a novel ortho-para relationship and the para/meta ratio of substituent effects for mechanism elucidation

Article abstract of DOI:10.1021/jo0706224

(Graph Presented) Rate constants were measured for the oxidative chlorodehydrogenation of (R,S)-2-phenoxypropanoic acid and nine ortho-, ten para- and five meta-substituted derivatives using (R,S)-1-chloro-3-methyl-2,6- diphenylpiperidin-4-one (NCP) as chlorinating agent. The kinetics was run in 50% (v/v) aqueous acetic acid acidified with perchloric acid under pseudo-first-order conditions with respect to NCP at temperature intervals of 5 K between 298 and 318 K, except at the highest temperature for the meta derivatives. The dependence of rate constants on temperature was analyzed in terms of the isokinetic relationship (IKR). For the 20 reactions studied at five different temperatures, tne isokinetic temperature was estimated to be 382 K, which suggests the preferential involvement of water molecules in the rate-determining step. The dependence of rate constants on meta and para substitution was analyzed using the tetralinear extension of the Hammett equation. The parameter λ for the para/meta ratio of polar substituent effects was estimated to be 0.926, and its electrostatic modeling suggests the formation of an activated complex bearing an electric charge near the oxygen atom belonging to the phenoxy group. A new approach is introduced for examining the effect of ortho substituents on reaction rates. Using IKR-determined values of activation enthalpies for a set of nine pairs of substrates with a given substituent, a linear correlation is found between activation enthalpies of ortho and para derivatives. The correlation is interpreted in terms of the selectivity of the reactant toward para- or ortho-monosubstituted substrates, the slope of which being related to the ortho effect. This slope is thought to be approximated by the ratio of polar substituent effects from ortho and para positions in benzene derivatives. Using the electrostatic theory of through-space interactions and a dipole length of 0.153 nm, this ratio was calculated at various positions of a charged reaction center along the benzene C₁-C₄ axis, being about 2.5 near the ring and decreasing steeply with increasing distance until reaching a minimum value of -0.565 at 1.3 nm beyond the aromatic ring. Activation enthalpies and entropies were estimated for substrates bearing the isoselective substituent in either ortho and para positions, being demonstrated that they are much different from the values for the parent substrate. The electrophilic attack on the phenolic oxygen atom by the protonated chlorinating agent is proposed as the rate-determining step, this step being followed by the fast rearrangement of the intermediate thus formed, leading to products containing chlorine in the aromatic ring.

Full text of DOI:10.1021/jo0706224

Chlorination of 2-Phenoxypropanoic Acid with NCP in Aqueous
Acetic Acid: Using a Novel Ortho-Para Relationship and the
Para/Meta Ratio of Substituent Effects for Mechanism Elucidation
Manuel A. P. Segurado,*,† Joa˜o Carlos R. Reis,‡ Jaime D. Gomes de Oliveira,§
Senthamaraikannan Kabilan,*,| and Manohar Shanthi|
Centro de Cieˆncias Moleculares e Materiais and Faculdade de Farma´cia, UniVersidade de Lisboa, AV.
Prof. Gama Pinto, 1649-003 Lisboa, Portugal, Departamento de Qu´ımica e Bioqu´ımica, Faculdade de
Cieˆncias, UniVersidade de Lisboa, Portugal, Instituto Superior de Engenharia de Lisboa, Portugal, and
Department of Chemistry, Annamalai UniVersity, Annamalai Nagar 608002, India
asegurado@ff.ul.pt; kabilan@sify.com
ReceiVed March 26, 2007
Rate constants were measured for the oxidative chlorodehydrogenation of (R,S)-2-phenoxypropanoic acid and
nine ortho-, ten para- and five meta-substituted derivatives using (R,S)-1-chloro-3-methyl-2,6-diphenylpiperidin-
4-one (NCP) as chlorinating agent. The kinetics was run in 50% (v/v) aqueous acetic acid acidified with
perchloric acid under pseudo-first-order conditions with respect to NCP at temperature intervals of 5 K between
298 and 318 K, except at the highest temperature for the meta derivatives. The dependence of rate constants
on temperature was analyzed in terms of the isokinetic relationship (IKR). For the 20 reactions studied at five
different temperatures, the isokinetic temperature was estimated to be 382 K, which suggests the preferential
involvement of water molecules in the rate-determining step. The dependence of rate constants on meta and
para substitution was analyzed using the tetralinear extension of the Hammett equation. The parameter λ for
the para/meta ratio of polar substituent effects was estimated to be 0.926, and its electrostatic modeling suggests
the formation of an activated complex bearing an electric charge near the oxygen atom belonging to the phenoxy
group. A new approach is introduced for examining the effect of ortho substituents on reaction rates. Using
IKR-determined values of activation enthalpies for a set of nine pairs of substrates with a given substituent,
a linear correlation is found between activation enthalpies of ortho and para derivatives. The correlation is
interpreted in terms of the selectivity of the reactant toward para- or ortho-monosubstituted substrates, the
slope of which being related to the ortho effect. This slope is thought to be approximated by the ratio of polar
substituent effects from ortho and para positions in benzene derivatives. Using the electrostatic theory of through-
space interactions and a dipole length of 0.153 nm, this ratio was calculated at various positions of a charged
reaction center along the benzene C1-C4 axis, being about 2.5 near the ring and decreasing steeply with
increasing distance until reaching a minimum value of -0.565 at 1.3 nm beyond the aromatic ring. Activation
enthalpies and entropies were estimated for substrates bearing the isoselective substituent in either ortho and
para positions, being demonstrated that they are much different from the values for the parent substrate. The
electrophilic attack on the phenolic oxygen atom by the protonated chlorinating agent is proposed as the rate-
determining step, this step being followed by the fast rearrangement of the intermediate thus formed, leading
to products containing chlorine in the aromatic ring.
Introduction
process resulting in the formation of a new carbon-chlorine
bond.1 There is, however, a variety of reaction paths leading to
this structural feature, which depend on the nature of reactants
and substrates, as well as on the reaction conditions.1 Recently,
we investigated the reaction mechanism for the chlorination (or
Chlorination, as a particular case of halogenation, is a general
term employed in organic chemistry to qualify the oxidative
* Corresponding author.
† Faculdade de Farma´cia, Universidade de Lisboa.
‡ Faculdade de Cieˆncias, Universidade de Lisboa.
§ Instituto Superior de Engenharia de Lisboa.
| Annamalai University.
(1) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley: New York, 2007.
10.1021/jo0706224 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/13/2007
J. Org. Chem. 2007, 72, 5327-5336
5327

Segurado et al.
SCHEME 1. Chemical Structure of Reactants
1-Chloro-3-methyl-2,6-diphenylpiperidin-4-one (NCP) and
2-(Monosubstituted phenoxy)propanoic Acid (2-PPA)
sense, it is used for identifying the peculiarity of substituent
effects on rates and equilibria of ortho-substituted benzene
derivatives. We address the ortho effect from a restricted point
of view. Instead of attempting a conventional Hammett-like
approach using ortho-substituent constants, or a multiparametric
correlation including steric constants, we focus on extrather-
modynamic correlations among activation parameters for ortho
and para derivatives within a single reaction series. This
approach may be seen as an application of the isoselective
relationship18,19 if we think in terms of competition between
ortho and para derivatives toward a given reactant. From an
isokinetic temperature of 382 K, we infer an activated complex
preferentially solvated by molecules of water. From the effect
of meta and para substitution on reaction rates, we find evidence
for the presence of a positive electric charge near the ether
oxygen atom in the transition state. From a stimulating linear
correlation of IKR-determined activation enthalpies for ortho-
substituted substrates against para-substituted substrates with
the same substituent, we develop a method for addressing the
ortho effect and enquire into the ortho/para ratio of polar
substituent effects. By drawing together the results of these
analyses, we propose a three-step mechanism for the chlorination
of 2-PPA with NCP.
chloro-dehydrogenation1) of N-phenylbenzenesulfonamide using
an equilibrium mixture of different conformations of the racemic
(R,S)-1-chloro-3-methyl-2,6-diphenylpiperidin-4-one (NCP)
(Scheme 1) as chlorinating agent in aqueous acetic acid.2 Since
azacyclohexane is the alternative name of the cyclic secondary
amine piperidine, NCP can also be designated as (R,S)-1-chloro-
3-methyl-2,6-diphenylazacyclohexan-4-one. NCP is an interest-
ing mild oxidant and chlorinating reagent, which was first
synthesized as a new compound by Ganapathy and Vijayan3
from the reaction of (R,S)-3-methyl-2,6-diphenylpiperidin-4-one
with Chloramine-T. NCP is a very stable crystalline solid and
has been used as a reactant to oxidize3-7 or chlorinate2,8-10
various organic substrates.
Results and Discussion
Rate Constants. Experimental pseudo-first-order rate con-
stants with respect to NCP, kobs, were determined at temperatures
between 298 and 318 K for the chlorination of 25 2-phenox-
ypropanoic acids (2-PPA) with NCP in aqueous acetic acid
further acidified with perchloric acid (150 mmol dm-3).
Preliminary experiments at 303 K also demonstrated first-order
kinetics with respect to 2-PPA and to the hydronium ion. For
the latter experiment, which showed that the reaction is acid-
catalyzed, the concentration of perchloric acid was varied
between 50 (pH ) 1.30) and 250 mmol dm-3 (pH ) 0.60). At
pH ) 0.80, second-order rate constants k2 were calculated
according to eq 1, where [2-PPA]0 stands for the initial
concentration of the substrate at ambient temperature. In fact,
under these acidic conditions, substrates, which are weak organic
acids, should remain undissociated during the course of the
reaction.
In the present research we selected the racemic (R,S)-2-
phenoxypropanoic acid (2-PPA) (Scheme 1) as substrate and
kept unchanged most of the reaction conditions used in the
previous study.2 We note that the effective herbicide dichlorprop
is chemically (R,S)-2-(2,4-dichlorophenoxy)propanoic acid,
although only the R enantiomer is active. Understanding the
chemistry of 2-PPA, which is its parent compound, is of interest
because there is an environmental concern about contamination
of soil and groundwater by pesticides. To probe the mechanism
of the reaction between NCP and 2-PPA, we examined
substituent effects by measuring rate constants for a total of 25
substrates in 50% (v/v) aqueous acetic acid solutions in the
temperature range of 298-318 K. The correlation analysis of
this extensive kinetic data was made in terms of the isokinetic
relationship (IKR),11-13 the para/meta ratio of substituent
effects,14-16 and a new ortho-para relationship. The term ortho
effect has a long tradition in organic chemistry.17 In a broad
k2 ) kobs/[2-PPA]0
(1)
(2) Reis, J. C. R.; Segurado, M. A. P.; de Oliveira, J. D. G.; Kabilan, S.;
Suganya, K. Collect. Czech. Chem. Commun. 2004, 69, 2253-2275.
(3) Ganapathy, K.; Vijayan, B. J. Indian Chem. Soc. 1978, 55, 957-
959.
Rate constants k2, expressed in the temperature-independent
units20 dm3 mol-1 s-1, are reported in Table 1, where 2-phe-
noxypropanoic acids are classified according to the special14
or normal23 nature of the substituent on the phenyl ring.
Isokinetic Relationship. The isokinetic relationship is a
powerful tool for the correlation analysis of reaction series.11-13
(4) Ganapathy, K.; Kabilan, S. Int. J. Chem. Kinet. 1989, 21, 423-430.
(5) Kabilan, S.; Sengu, P.; Sankar, P.; Krishnasamy, K. Oxid. Commun.
1993, 16, 339-345.
(6) Kabilan, S.; Vasanthi, G.; Suganya, K.; Palanivel, C. Oxid. Commun.
2000, 23, 524-531.
(7) Balasubramanian, S.; Ramalingan, C.; Kabilan, S. Synth. Commun.
2003, 33, 2979-2984.
(16) Reis, J. C. R.; Segurado, M. A. P.; de Oliveira, J. D. G. J. Phys.
Org. Chem. 1998, 11, 495-503.
(17) Shorter, J. In AdVances in Linear Free Energy Relationships;
Chapman, N. B., Shorter, J., Eds.; Plenum Press: New York, 1972; pp
71-117.
(18) Giese, B. Angew. Chem., Int. Ed. Engl. 1977, 16, 125-136.
(19) Giese, B. Acc. Chem. Res. 1984, 17, 438-442.
(20) Hamann, S. D.; le Noble, W. J. J. Chem. Educ. 1984, 61, 658-
660.
(21) Sjo¨stro¨m, M.; Wold, S. Chem. Scr. 1976, 9, 200-210.
(22) Exner, O. Correlation Analysis of Chemical Data; Plenum Press:
New York, 1988.
(8) Ganapathy, K.; Ilango, C. J. Indian Chem. Soc. 1986, 63, 1052-
1054.
(9) Ganapathy, K.; Palaniappan, A. N. Int. J. Chem. Kinet. 1990, 22,
415-426.
(10) Kabilan, S.; Sankar, P.; Krishnasamy, K. Oxid. Commun. 1994, 17,
115-122.
(11) Exner, O. Prog. Phys. Org. Chem. 1973, 10, 411-482.
(12) Linert, W. Chem. Soc. ReV. 1994, 23, 429-438.
(13) Liu, L.; Guo, Q.-X. Chem. ReV. 2001, 101, 673-695.
(14) Reis, J. C. R.; Segurado, M. A. P.; de Oliveira, J. D. G. J. Phys.
Org. Chem. 1995, 8, 5-14.
(15) Reis, J. C. R.; Segurado, M. A. P.; de Oliveira, J. D. G. J. Phys.
Org. Chem. 1995, 8, 671-688.
(23) Exner, O. In Correlation Analysis in Chemistry: Recent AdVances;
Chapman, N. B., Shorter, J., Eds.; Plenum Press: New York, 1978; pp
439-540.
5328 J. Org. Chem., Vol. 72, No. 14, 2007

Chlorination of 2-Phenoxypropanoic Acid with NCP
TABLE 1. Second-Order Rate Constants k2 at Different Temperatures for the Chlorination of 25 2-(Monosubstituted phenoxy)propanoic
Acids (2-PPA) with NCP in 50% (v/v) Aqueous Acetic Acid Acidified with Perchloric Acid
k2/(10-3 dm3 mol-1 s-1
)
substituent
σ0 a
σBA b
298.15 K
303.15 K
308.15 K
313.15 K
318.15 K
special
m-OCH3
m-Cl
0.102
0.365
0.369
5.96
2.101
1.67
30.23
19.26
2.99
7.94
2.81
2.231
35.5
11.92
4.21
3.342
41.5
27.56
5.69
5.15
6.35
5.75
1.98
1.88
15.89
5.62
4.463
48.28
32.71
7.72
7.06
8.04
7.27
2.927
2.622
m-Br
p-OCH3
p-OC2H5
p-Cl
-0.28
55.9
23.1
38.61
10.48
9.58
9.97
9.21
0.22
0.22
4.143
3.708
5.00
4.50
1.32
p-Br
2.65
o-OCH3
o-OC2H5
o-Cl
3.915
3.507
0.865
0.815
4.305
3.78
o-Br
1.22
normal
H
0
6.50
11.89
0.480
15.12
13.39
1.383
1.227
1.277
0.417
2.93
8.13
15.86
0.630
18.21
16.29
2.051
1.836
1.905
0.650
3.90
10.11
23.78
0.950
21.79
19.7
3.008
2.72
2.813
1.00
5.16
5.00
1.13
1.15
12.43
31.69
1.261
25.94
23.68
4.366
3.99
4.112
1.513
6.78
15.8
m-CH3
m-NO2
p-CH3
p-C2H5
p-CHO
p-CO2H
p-CO2CH3
p-NO2
o-CH3
o-C2H5
o-CO2H
o-CO2CH3
o-NO2
-0.062
0.713
-0.135
-0.127
0.437
0.440
0.441
0.814
30.72
28.33
6.23
5.75
5.93
2.27
8.85
8.85
2.70
3.70
6.71
1.72
1.74
0.822
0.465
0.484
0.176
0.731
0.751
0.300
2.585
2.585
1.323
0.500
a Unified σ0 substituent constants.21 b Hammett, benzoic acid reactivity σBA substituent constants,22 for those substituents where σBA differs from σ0.
In this similarity technique, the effect of temperature on the
series reaction constants is tested using11,24
which is a substituent-independent constant. Brown27 interpreted
this quantity as an “intrinsic” Gibbs energy of activation because
it would equal the activation enthalpy of a hypothetical
derivative having zero activation entropy.
log(kij/Tj) ) aIKR + bi(Tj-1 - âIKR
)
(2)
-1
∆qGi° ) ∆qHi° - T ∆qSi°
(4)
If the latter equation is statistically validated, then the reaction
series is described by a set of straight lines having slopes bi,
which intersect at a common point. The temperature corre-
sponding to the intersecting point is designated as the isokinetic
temperature, âIKR, the ordinate being log(kiso,â(IKR)/âIKR). This
ordinate has been termed by Linert and Sapunov25 as an
“invariant point” for a given chemical reaction series. Indeed,
as shown by these authors,25 this ordinate value will be the same
in different isoparametric relationships representing temperature-
dependent data for the reaction series and may be used for
estimating the isosubstituent Hammett constant.26
We tested for an IKR our kinetic data for the parent
compound and all of its ortho and para derivatives, totaling 20
reactions at five different temperatures. Equation 2 was fitted
to these data in Table 1 using the program IKR-80-20 for the
least-squares linear regression with a common point of intersec-
tion.24 This program yielded standard deviations s00 ) 0.0027
for unconstrained straight lines in terms of eq 5, which expresses
Eyring’s plots, and s0 ) 0.0168 for the IKR-constrained straight
lines in eq 2. Although these statistics would imply rejecting
an isokinetic relationship, in terms of Exner’s Ψ-test,28,29 the
IKR equation is validated as an approximate relationship (Ψ )
0.031). The strict criterion used in the IKR-80-20 program has
been noted before by various authors,2,24,30 and the possible
occurrence of an IKR is sometimes assessed by visual appraisal
of an Arrhenius plot for the reaction series.31,32
âIKR is also the slope for the linear correlation between
standard enthalpies of activation ∆qHi° and standard entropies
of activation ∆qSi° of the individual reactions in the series,
according to
∆qHi° ) hâ(IKR) + âIKR∆qSi°
(3)
log(kj/Tj) ) a + bTj-1
(5)
We note that, in spite of recent doubts,13 the validation of an
IKR in terms of eq 2 necessarily entails the occurrence of an
enthalpy-entropy compensation effect as expressed by eq 3.
In view of eq 4 where ∆qGi° is the standard Gibbs energy of
activation, the intercept hâ(IKR) in eq 3 equals ∆qGi° (T ) âIKR),
For the probable IKR describing the 20 chlorination reactions
under examination, the main best fitting parameters in eq 2 are
(27) Brown, R. F. J. Org. Chem. 1962, 27, 3015-3026.
(28) Exner, O. Collect. Czech. Chem. Commun. 1966, 31, 3222-3251.
(29) Exner, O. Collect. Czech. Chem. Commun. 1974, 39, 515-527.
(30) Ventura, C.; Jiang, W.-Q.; Albuquerque, L.; Gonc¸alves-Maia, R.;
Maia, H. L. S. J. Pept. Sci. 2006, 12, 239-242.
(31) Karunakaran, C.; Suresh, S. Int. J. Chem. Kinet. 2005, 37, 5-9.
(32) Karunakaran, C.; Suresh, S. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 2005, 44, 1277-1282.
(24) Ouvrard, C.; Berthelot, M.; Lamer, T.; Exner, O. J. Chem. Inf.
Comput. Sci. 2001, 41, 1141-1144.
(25) Linert, W.; Sapunov, V. N. Chem. Phys. 1988, 119, 265-274.
(26) Linert, W. Aust. J. Chem. 1986, 39, 198-208.
J. Org. Chem, Vol. 72, No. 14, 2007 5329

Segurado et al.
TABLE 2. Standard Enthalpies of Activation ∆qH° and Standard
Entropies of Activation ∆qS° Derived from Equations 2 and 5 for
the Chlorination of 2-Phenoxypropanoic Acids with NCP in
Aqueous Acetic Acid
aIKR ) -0.730 and âIKR ) 382 K. At 95% confidence level,
the isokinetic temperature is expected to be between 376 and
398 K. We interpret this value for âIKR in terms of Linert’s
theory,33-36 according to which solvents act as heat baths for
activated processes in solution. Linert’s expression between
isokinetic temperatures and active vibration frequencies of
solvent molecules has been recast37 in terms of wavenumbers
ν˜ as in eq 6. For âIKR ) 382 K, eq 6 yields the wavenumber of
∆qH°/(kJ mol-1
eq 2 eq 5
)
∆qS°/(J K-1 mol-1
eq 2 eq 5
)
substituent
special
m-OCH3
m-Cl
52.06 ( 2.20
52.14 ( 2.14
52.09 ( 2.16
21.69 ( 0.01
24.87 ( 0.01
46.83 ( 0.15
48.14 ( 0.04
34.43 ( 0.17
35.46 ( 0.14
60.64 ( 0.10
57.94 ( 1.14
-113.2 ( 7.2
-121.6 ( 7.0
-123.7 ( 7.0
-201.3 ( 0.1
-194.4 ( 0.1
-136.2 ( 0.5
-132.8 ( 0.2
-175.5 ( 0.6
-173.0 ( 0.5
-100.2 ( 0.4
-109.6 ( 3.7
265 cm-1
.
m-Br
p-OCH3
p-OC2H5
p-Cl
17.44
22.83
43.77
45.13
42.15
43.45
57.80
58.88
-215.1
-201.0
-146.2
-142.6
-150.4
-147.0
-109.4
-106.6
ν˜heat bath/cm-1 ) 0.695(âIKR/K)
(6)
p-Br
The present kinetics were run in a mixture of water and acetic
acid. Having examined the infrared spectrum of acetic acid, only
absorption bands at wavenumbers larger than 450 cm-1 were
observed. On the other hand, liquid water presents an intense
absorption band from 300 to 900 cm-1, which has been ascribed
to the bending of hydrogen bonds.38 Following the suggestion
by a reviewer, we also examined the Raman spectrum of liquid
water. At 303 K, Carey and Korenowski39 observed a Raman
peak centered at 425 cm-1, which corresponds to one of the
three intermolecular librational modes that are Raman active.
The value of 265 cm-1 compares well with active vibrational
wavenumbers for various chemical reactions in water,40,41 and,
although displaced to lower wavenumbers, it is in fair agreement
with the wavenumber of 357 cm-1 found for a similar
chlorination reaction series in the same solvent mixture.2 On
the basis of the foregoing discussion, we interpret the isokinetic
temperature of 382 K as indicating preferential solvation of
activated complexes by water molecules.
o-OCH3
o-OC2H5
o-Cl
o-Br
normal
H
m-CH3
m-NO2
p-CH3
p-C2H5
p-CHO
p-CO2H
p-CO2CH3
p-NO2
o-CH3
o-C2H5
o-CO2H
o-CO2CH3
o-NO2
35.97
32.14 ( 0.66
52.05 ( 2.21
51.76 ( 2.50
25.39 ( 0.01
26.99 ( 0.01
56.85 ( 0.07
58.44 ( 0.08
58.01 ( 0.07
64.23 ( 0.05
41.02 ( 0.11
44.23 ( 0.15
65.10 ( 0.09
63.56 ( 0.08
76.99 ( 0.13
-166.6
-179.0 ( 2.2
-107.5 ( 7.2
-135.2 ( 8.2
-194.6 ( 0.1
-190.3 ( 0.1
-109.0 ( 0.3
-104.7 ( 0.3
-105.8 ( 0.3
-94.2 ( 0.2
-155.9 ( 0.4
-145.7 ( 0.5
-90.4 ( 0.3
-95.2 ( 0.3
-58.6 ( 0.5
25.91
27.25
52.27
53.60
53.15
66.78
44.94
45.44
65.20
64.93
76.03
-192.9
-189.4
-123.9
-120.4
-121.6
-85.9
-143.1
-141.8
-90.0
-90.7
-61.7
in these exceptions, a situation also encountered in a similar
study.2 These deviations may reflect the possible formation of
intermolecular hydrogen bonds between o-alkoxy groups and
protic solvent molecules near the reaction site.43 We also note
that the magnitude and sign of the activation entropy of a
second-order reaction in solution depend on the chosen standard
state,44 which can be identified from the units expressing rate
constants.
In a reaction series, Exner11,45 has suggested IKR-constrained
activation parameters to be nearer to “true” values than
conventional values individually calculated in terms of Eyring
equation. In support of Exner’s proposal, Segura46 found for a
certain reaction series that experimental isokinetic activation
enthalpies correlated much better with theoretically computed
energies using an ab initio molecular-orbital method than do
experimental Eyring’s activation enthalpies. The discussion that
follows will be based on isokinetic activation parameter values,
although it refers occasionally to Eyring’s values.
Activation Parameters. Standard enthalpies and entropies
of activation were computed for all of the 25 chlorination
reactions from the individual temperature dependence of their
rate constants in terms of the Eyring equation written in the
form of eq 5. As Lente et al.42 commented recently, ∆qS° values
calculated from the best fitting parameters in eq 5 are as reliable
as the corresponding ∆qH° values. These activation parameters
and their standard deviations are given in Table 2 along with
of the corresponding IKR-constrained values for the 20 reactions
examined with this technique. Isokinetic activation enthalpies
and entropies were calculated from the best fitting parameters
in eq 2 using eqs 7 and 8, in which R is the gas constant, h is
the Planck constant, and kB is the Boltzmann constant.
∆qHi° ) -2.303Rbi
(7)
(8)
∆qSi° ) -2.303R[log(h/kB) + aIKR - bi/âIKR
]
Tetralinear Analysis of Meta and Para Substituent Effects.
The Hammett-like analysis of substituent effects from meta and
para positions on the present chlorination reaction was done
using our tetralinear approach,15 in which the meta-para
interrelationship is constrained by a hyperbolic model.14 Since
this approach has been described before in detail and applied
to various reaction series,2,15,16,47,48 only a brief account is given
In relation to Eyring’s values, the isokinetic values of
activation enthalpies and entropies generally differ by less than
10%, except for ∆qH° of four reactions and ∆qS° of five
reactions. We note that both o-alkoxy derivatives are included
(33) Linert, W. Chem. Phys. 1987, 114, 449-455.
(34) Linert, W. Chem. Phys. 1987, 116, 381-389.
(35) Linert, W. Chem. Phys. 1989, 129, 381-393.
(36) Linert, W. Collect. Czech. Chem. Commun. 1990, 55, 21-31.
(37) Pinheiro, L. M. V.; Calado, A. R. T.; Reis, J. C. R. Org. Biomol.
Chem. 2004, 2, 1330-1338.
(43) Kulha´nek, J.; Pytela, O. Collect. Czech. Chem. Commun. 1997, 62,
913-924.
(44) Abraham, M. H.; Nasehzadeh, A. J. Chem. Soc., Chem. Commun.
1981, 905-906.
(45) Exner, O. Collect. Czech. Chem. Commun. 1972, 37, 1425-1444.
(46) Segura, P. Collect. Czech. Chem. Commun. 1985, 50, 1565-1572.
(47) Segurado, M. A. P.; Reis, J. C. R.; de Oliveira, J. D. G. J. Chem.
Soc., Perkin Trans. 2 2002, 323-328.
(38) Eisenberg, D.; Kauzmann, W. The Structure and Properties of
Water; Oxford University Press: New York, 1969.
(39) Carey, D. M.; Korenowski, J. Chem. Phys. 1998, 108, 2669-2675.
(40) Linert, W. Chem. Phys. 1989, 129, 381-393.
(41) Linert, W.; Jameson, R. F. Chem. Soc. ReV. 1989, 18, 477-505.
(42) Lente, G.; Fa´bian, I.; Poe¨, A. J. New J. Chem. 2005, 29, 759-760.
5330 J. Org. Chem., Vol. 72, No. 14, 2007

Chlorination of 2-Phenoxypropanoic Acid with NCP
TABLE 3. Tetralinear Analysis of the Chlorination Rates of 2-(m- and p-Monosubstituted phenoxy)propanoic Acids with NCP in Aqueous
Acetic Acid at Different Temperaturesa
temperature/K
parameter
298.15
303.15
308.15
313.15
λ
0.967 ( 0.058
0.474 ( 0.037
-2.105 ( 0.180
0.064
0.900 ( 0.056
0.454 ( 0.039
-2.016 ( 0.184
0.066
0.912 ( 0.042
0.432 ( 0.037
-1.919 ( 0.178
0.063
0.846 ( 0.067
0.415 ( 0.037
-1.8422 ( 0.175
0.066
γ
γ/γ0
sb
a Data from Table 1 in the form log(k2,X/k2,H) fitted to the constrained tetralinear equation (eqs 9-12) using σ0 constants21 and σBA constants.22 Data
points for the m-CH3 derivative were excluded at 308.15 and 313.15 K. b Standard deviation of the fit.
herein. Thus, normal substituents, which are defined by Exner23
as dipolar groups bearing a full octet without lone pairs of
electrons on the atom next to the aromatic ring, are treated
separately from special substituents,14 which either bear a lone
electron pair or an incomplete electron octet on that atom.
Because this separation applies to both meta and para positions,
there are four basic linear correlations, each involving only meta
normal (3n), para normal (4n), meta special (3s), or para special
(4s) substituents.
calculated using a Monte Carlo procedure previously de-
scribed.16,47
The λ values in Table 3 do not show significant dependence
on temperature. In fact, the difference between any two of these
values is within the combined standard errors. They will be used
in the electrostatic modeling of parameter λp/m determined by
charged activated complexes formed during the oxidative
chlorination of the 2-phenoxypropanoic acid. Since γ/γ° can
be interpreted as a Hammett reaction constant F, its relatively
large and negative value indicates the presence of an electron-
deficient center in transition states. Preliminary fitting experi-
ments using the Yukawa-Tsuno version of the tetralinear
equation16 showed that the present reaction series could be
equally well-described using the σ+ scale of substituent constants
in conjunction with a resonance-demand parameter r+ of 0.28.
We have already shown that the σBA scale is equivalent to the
σ+ scale with r+ ) 0.215.16 We conclude that there is a moderate
through-resonance demand toward a partial positive charge
during the course of the chlorination reaction under examination.
For approximately locating the reaction site, we resort to the
information contained in parameter λ. This is done using a
previously developed treatment for the para/meta ratio of polar
substituent effects in terms of the electrostatic theory,15,47 which
was recently reexamined2 in the light of Exner and Bo¨hm’s
calculation of interaction energies using the density functional
theory.49,50 We note that, since about 56% of the total interaction
energy between a dipole µX and a charge can be described by
direct through-space electrostatic interactions,2 then for interac-
tions of a given type the ratio of electrostatic energies should
In its version for Hammett analyses, the basic tetralinear
equation is given by15
log(k3n/kH) ) δ3n + F3nσ3n°
log(k4n/kH) ) δ4n + F4nσ4n°
(9)
(10)
log(k3s/kH) ) δ3s + F3sσ3s°
(11)
(12)
BA
log(k4s/kH) ) δ4s + F4sσ4s
Although there are eight fitting parameters in eqs 9-12, only
four of them are independent parameters by virtue of four
constraining equations deduced from the hyperbolic model for
the meta-para interrelationship of substituent effects.15 Two
of these constraints yield the relevant model parameters λ and
γ in terms of eqs 13 and 14, where λ° ) 0.961 and γ° )
-0.225 are constants for the hyperbolic model applied14,16 to
the unified σ° scale.21 Parameter λ is effectively λp/m, i.e., the
para/meta ratio of polar, inductive substituent effects, and the
quantity γ/γ° has been shown to be an analogue of the Hammett
reaction constant after excluding through-resonance substituent
effects.2,15,16,48
give a reliable measure of the relative total interaction energy.
15,47
This modeling is based on eq 15 for λp/m
,
where distance
r+ is measured from the positive pole, which can be either on
the substituent charge center or on a ring carbon atom, to the
charge on the reaction site, and similarly for distance r-.
F4n/F3n ) F4s/F3s ) λ/λ°
(13)
λ
p/m(µX, charge) ) (1/r+ - 1/r-)para/(1/r+ - 1/r-)meta (15)
For the experimental parameter λ, in Table 3 we report values
2δ4n - δ3nλ + F4nγ° ) 2δ4s - δ3sλ + F4sγ° ) γ (14)
ranging between 0.846 and 0.967. Modeling of these values with
eq 15 gives a broad range of positions for locating the charge.
However, disregarding the λ value at the highest temperature,
we obtain an average value of 0.926, which indicates a position
0.136 nm away the benzene ring on its C1-C4 axis. Incidentally,
this is equal to the interatomic distance C1-O. Hence, this
analysis points to the presence of an electric charge very near
the oxygen atom belonging to the phenoxy group of activated
complexes.
We used our nonlinear least-squares computing program15,16
for the constrained fitting of eqs 9-12 to the kinetic data in
Table 1 at each of the experimental temperatures where meta
and para derivatives were investigated. However, the p-OC2H5
derivative was excluded from this analysis for lack of the
corresponding σBA constant. We searched for outlier data points
exhibiting a deviation larger than twice the standard deviation
of the fit. This search identified the m-CH3 derivative at 308.15
and 313.15 K. After removing these two data points, the best
values for the tetralinear parameters of the present reaction series
are reported in Table 3, together with their standard deviations
The evidence so far collected strongly suggests the electro-
philic attack of protonated NCP on the substrate phenolic oxygen
atom as the rate-determining step of this chlorination reaction.
(48) Kabilan, S.; Girija, R.; Reis, J. C. R.; Segurado, M. A. P.; de
Oliveira, J. D. G. J. Chem. Soc., Perkin Trans. 2 2002, 1151-1157.
(49) Exner, O.; Bo¨hm, S. Chem. Eur. J. 2003, 9, 4718-4723.
(50) Exner, O.; Bo¨hm, S. J. Phys. Org. Chem. 2004, 17, 124-130.
J. Org. Chem, Vol. 72, No. 14, 2007 5331

Segurado et al.
TABLE 4. Correlation Analysis of an Interdependence between Activation Enthalpies for Ortho and Para Derivatives in Terms of Equation
16 for Two Reaction Series
chlorination reaction series
2-phenoxypropanoic acids
na
∆qH° calculated using
hR/(kJ mol-1
)
a
rb
9
9
12
12
eq 2
eq 5
eq 2
eq 5
27.24 ( 0.97
16.46 ( 2.79
14.16 ( 1.07
11.31 ( 3.12
0.713 ( 0.026
0.884 ( 0.071
0.928 ( 0.018
0.913 ( 0.051
0.995
0.978
0.998
0.985
N-phenylbenzenesulfonamidesc
a Number of data points. b Correlation coefficient. c Activation enthalpy values taken from ref 2.
Ortho-Para Relationship. We use the unclear51 term ortho
effect as a short name for the change on chemical properties of
benzene derivatives occurring on replacement of an o-hydrogen
by different substituents. A variety of treatments have been
developed over decades to tackle this elusive effect. We refer
to Exner and associate51-53 and Pytela and co-workers54,55 for
concise accounts of older approaches to the ortho effect. Here
we follow a modern trend which concentrates on comparing
the reactivity of ortho and para derivatives within a given
reaction series.51,52,55,56 Indeed, excluding specific interactions
with the reaction center, substituent effects from the alternating
ortho and para positions have the same nature, as Pytela and
Prusek55 have noted. Curiously, the idea that the reactivity of
para derivatives provides a basis for interpreting the reactivity
of ortho derivatives is a revival of the very first approach to
the ortho effect.17
Ortho versus Para Activation Enthalpies. The present
chlorination reaction series contains nine different substituents
s in both the ortho and para positions, and an IKR holds
approximately in this series. Hence, two subreaction series can
be formed in which the common variable is the substituent
nature. For reasons discussed later, the “substituent” hydrogen
is not included in this analysis. Aiming at probing a possible
correlation between ∆qH°ortho-s and ∆qH°para-s, we tested a linear
model in terms of eq 16 where both variables are interdependent.
FIGURE 1. Correlation of activation enthalpies for the chlorination
of 2-(o- versus p-monosubstituted phenoxy)propanoic acids. Data points
from Table 2: filled circles, IKR values (eq 2); full line, best straight
line through filled circles; open circles, Eyring values (eq 5); filled
diamond, IKR value for the parent 2-PPA; open diamond, Eyring value
for the parent 2-PPA. Filled triangle, calculated common ortho and
para activation enthalpies for derivatives bearing the isoselective
substituent (see later).
These interesting linear correlations prompted us to develop
an extrathermodynamic formalism to frame these results. In the
following we explore the consequences of eq 16 being obeyed
within a given reaction series. Since both ortho and para subsets
pertain to the same IKR, then eqs 17 and 18 hold. In other
words, eqs 17 and 18 are particular cases of eq 3.
∆qH°ortho-s ) hR + R∆qH°para-s
(16)
For the correlation analysis of chemical data with similar
experimental errors on either variable, Exner and Zva´ra57
recommend using the squared perpendicular distances from the
regression line as the least-squares condition. In the context of
nonlinear regressions, we have already used the least sum of
rectangle areas defined by the orthogonal distances from the
regression curve.14,58 In the linear case of eq 16 both methods
become identical for regression lines of unit slope. For con-
venience we preferred the least-rectangles linear regression
analysis, details of which are given in the Experimental Section.
This analysis was performed with isokinetic and Eyring
activation enthalpies for the present and a related reaction series.
Results are summarized in Table 4 and shown in Figure 1 for
the 2-phenoxypropanoic acid series.
∆qH°ortho-s ) hâ(IKR) + âIKR∆qS°ortho-s
∆qH°para-s ) hâ(IKR) + âIKR∆qS°para-s
(17)
(18)
Combination of eqs 16-18 yields eq 19, in which the
intercept sR is given by eq 20.
∆qS°ortho-s ) sR + R∆qS°para-s
sR ) [hR - (1 - R)hâ(IKR)]/âIKR
(19)
(20)
Additionally, in view of the general thermodynamic relation-
ship given in eq 4, activation Gibbs energies ∆qG°ortho and
∆qG°para became linked by eq 21, the intercept gR being defined
in eq 22.
(51) Bo¨hm, S.; Fiedler, P.; Exner, O. New J. Chem. 2004, 28, 67-74.
(52) Exner, O.; Bo¨hm, S. Curr. Org. Chem. 2006, 10, 763-778.
(53) Fiedler, P.; Bo¨hm, S.; Kulha´nek, J.; Exner, O. Org. Biomol. Chem.
2006, 4, 2003-2011.
∆qG°ortho-s ) gR + R∆qG°para-s
gR ) hR - TsR
(21)
(22)
(54) Pytela, O.; Lisˇka, J. Collect. Czech. Chem. Commun. 1994, 59,
2005-2021.
(55) Pytela, O.; Prusek, O. Collect. Czech. Chem. Commun. 1999, 64,
1617-1627.
(56) Exner, O.; Bo¨hm, S. Collect. Czech. Chem. Commun. 2006, 71,
1239-1255.
Interestingly, linear eqs 16, 19, and 22 have the same slope,
R. As Exner commented,45 if the IKR holds for a reaction series,
∆qG°, ∆qH°, and ∆qS° change in a parallel manner so that
(57) Exner, O.; Zva´ra, K. J. Phys. Org. Chem. 1999, 12, 151-156.
(58) Reis, J. C. R.; Segurado, M. A. P.; de Oliveira, J. D. G. Collect.
Czech. Chem. Commun. 1999, 64, 1607-1616.
5332 J. Org. Chem., Vol. 72, No. 14, 2007

Chlorination of 2-Phenoxypropanoic Acid with NCP
SCHEME 2. Geometric Basis for Estimating the Ortho/
Para Ratio of Substituent Effects According to Equation 28
anyone of these activation parameters provide essentially the
same information. However, relative errors in activation en-
thalpies are smaller than in activation entropies. On the other
hand, although the intercepts hR and sR are temperature-
independent, gR is not. For these reasons we preferred using eq
16 to compute hR and R values.
Since the isokinetic temperature âIKR is independently
determined in terms of the IKR, a complete description of the
ortho-para relationship requires knowledge of the intercept
hâ(IKR) appearing in eq 3 for use in eq 20. This parameter is
conveniently derived from eqs 2, 7, and 8, being related to âIKR
and aIKR by
for the direct fit of eq 24 to our kinetic data; for example, Ψ )
0.110. No doubt this fact mirrors the increase in relative
experimental error occurring when passing from individual rate
constants to the ratio of rate constants.
Equation 27 is another consequence of an ISeR holding for
the OPR, which can be derived from eqs 17 and 18.
hâ(IKR) ) -2.303RâIKR[log(h/kB) + aIKR
]
(23)
Isoselective Relationship. There is a striking analogy
between the foregoing analysis of the ortho-para relationship
and the formalism developed for the isoselective relationship
(ISeR). The ISeR is a similarity technique18,19 for analyzing the
temperature effect on two reaction series possessing a common
variable that is useful in various chemical contexts.18,19,37,59
Selectivities should be expressed as the logarithm of the ratio
fast-to-slow reaction rate constants, and their temperature
dependence should follow a simple rule: the higher the
temperature, the lower the selectivity. We can thus define the
selectivity of a given reactant toward the para or ortho
substitution position in the substrate. In these terms the
corresponding ISeR is expressed by an analogue of eq 2, which
is written here in the form of eq 24 for application to the OPR.
∆qH°ortho-s - ∆qH°para-s ) âISeR(∆qS°ortho-s - ∆qS°para-s
)
(27)
Using isokinetic activation enthalpy and entropy values in
Table 2, we confirmed that the enthalpy-entropy plot of eq 27
gives the expected strictly linear fit (n ) 9, intercept ) -36 pJ
mol-1, âISeR ) 382 K, r ) 1.000). We note the vanishing
intercept value and an isoselective temperature equal to the iso-
kinetic temperature. Intriguingly, the excluded case of substituent
hydrogen would be accurately described by eq 27. However,
we shall present compelling arguments against including sub-
stituent hydrogen in the ortho/para relationship (OPR).
Ortho/Para Ratio of Polar Substituent Effects. In relation
to the para position, polar substituents in the ortho position are
nearer to the reaction center and their dipole orientation is much
different. These aspects of the ortho substitution are, of course,
well-known.17,61-63
Our electrostatic treatment of the para/meta ratio of polar
substituent effects is now extended to the OPR. Following
Dewar et al.,64 a polar substituent is approximated by a point
charge at its center of charges and an opposite point charge at
the neighbor carbon atom in the ring. From an average over 26
representative polar substituents,15 a dipole length of 0.153 nm
was estimated.47 In terms of the electrostatic theory underpinning
this model,47 the ortho/para ratio of electrostatic interaction
energies between a polar substituent X and a charged reaction
site, λo/p(µX, charge), is given by eq 28, which is an analogue
of eq 15.
log(kpara-sj/kortho-sj) ) aISeR + bs(Tj-1 - âISeR-1) (24)
In the latter equation âISeR is designated as the isoselective
temperature with respect to substituent variation. At this
temperature, the selectivity equals aISeR and will remain
unchanged upon substituent variation.
Exner and Giese60 established the conditions for the observa-
tion of an ISeR between two reaction series complying with
the IKR. One condition requires the same isokinetic temperature
for both series, in which case there exists an ISeR and âISeR
equals the common âIKR. A different and more general condition
requires the activation enthalpies of both series to be linearly
related to each other. Evidently, the former requirement is
automatically fulfilled in our approach to the OPR and the latter
requirement has been validated experimentally for two series
of chlorination reactions. Indeed, since ortho and para subseries
follow eq 2, we can write
log(kpara-sj/Tj) ) aIKR + bpara-s(Tj-1 - âIKR
)
(25)
(26)
-1
λo/p(µX, charge) ) (1/r+ - 1/r-)ortho/(1/r+ - 1/r-)para (28)
log(kortho-sj/Tj) ) aIKR + bortho-s(Tj-1 - âIKR
)
-1
The latter equation is obtained on the reasonable assumption
of identical effective permittivities for field effects from ortho
and para positions.
We calculated the parameter λo/p for charged reaction centers
at various distances d away the benzene ring along its C1-C4
axis, as depicted in Scheme 2. Duplicate calculations were also
Hence subtraction of eqs 25 and 26 yields an isoselective
equation having the form of eq 24, where bs ) bpara-s - bortho-s
and âISeR ) âIKR. Furthermore, in this particular case of an ISeR
between two subseries belonging to the same IKR, the intercept
aISeR ) aIKR - aIKR should ideally equal zero.
The versatile program IKR-80-20 has already been employed
for testing the ISeR.37 However, it gave poor correlation statistics
(61) Segura, P. J. Org. Chem. 1985, 50, 1045-1053.
(62) Bowden, K.; Grubbs, E. J. Prog. Phys. Org. Chem. 1993, 19, 183-
224.
(59) Alfaia, A. J. I.; Calado, A. R. T.; Reis, J. C. R. Eur. J. Org. Chem.
2000, 3627-3631.
(63) Bowden, K.; Grubbs, E. J. Chem. Soc. ReV. 1996, 25, 171-177.
(64) Dewar, M. J. S.; Golden, R.; Harris, J. M. J. Am. Chem. Soc. 1971,
93, 4187-4195.
(60) Exner, O.; Giese, B. Angew. Chem., Int. Ed. Engl. 1978, 17, 775-
777.
J. Org. Chem, Vol. 72, No. 14, 2007 5333

Segurado et al.
TABLE 5. Electrostatically Calculated Ortho/Para and Para/Meta
Ratios of Interaction Energy between a Charged Site and Polar
Substituents in Benzene Derivatives
suggests a value of 0.397 for this ratio. Nonetheless, the
corresponding λp/m values would be 0.944 and 0.985, respec-
tively, which show only a moderate disagreement. Approaching
again slope R in eq 16 by parameter λo/p, similar comparisons
for the two chlorination reaction series under examination give
a rough agreement. Thus, λp/m ) 0.926 for the chlorination of
2-phenoxypropanoic acid corresponds to λo/p ) 1.038 (see
Table 5), although we report R ) 0.713 in Table 4. For the
chlorination of N-phenylbenzenesulfonamide, we estimated2 λp/m
) 0.952, from which Table 5 indicates λo/p ) 0.713. The latter
value should be compared with R ) 0.928 in Table 4.
From this exploratory analysis based on scarce experimental
data, we draw the following conclusions. As advanced by Exner
and co-workers,51 slope R in eq 16 is determined, to a large
extent, by the ortho/para ratio of polar substituent effects.
However, the electrostatic modeling of slope R in terms of λo/p
did not give satisfactory concordance. Because λo/p values are
very sensitive to geometric conditions, this modeling should
be based on extremely accurate experimental data for rate and
equilibrium constants. Additionally, and perhaps more impor-
tantly, we should question the validity of assuming an average
dipole length for describing the polar effect of a collection of
different substituents from the ortho position in benzene
derivatives. This problem may also be compounded with the
remarkable recent finding by Exner and Bo¨hm65 that an
electronegativity term in the inductive effect of uncharged
groups becomes more important at short distances.
benzene derivative
pyridinium ion
d/nm
λo/p
λp/m
0.000
0.100
0.135
0.136
0.1397
0.1463
0.147
0.1594
0.170
0.200
0.213
0.229a
0.2322
0.292
0.300
0.400
1.300
2.538
1.441
1.048
1.038
1.000
0.934
0.928
0.810
0.713
0.482
0.397
0.296
0.279
0.000
-0.028
-0.282
-0.565
-0.500
0.835
0.898
0.925
0.926
0.929
0.934
0.934
0.944
0.952
0.976
0.985
0.998
1.000
1.045
1.050
1.119
1.482
2.000
anilinium ion
phenolate ion
benzoate ion
phenylacetate ion
∞
a For the orthogonal projection of charge center on the C1-C4 axis.
Case of “Substituent” o-Hydrogen. It is generally recog-
nized that approaches to the ortho effect based on Hammett-
like equations were the least successful.55 For example, Bowden
and Manser66 excluded the unsubstituted benzoic acid while
attempting to correlate the effect of ortho substituents with σ
constants for the corresponding para substituents. And Chapman
and co-workers67 noted that, in multiparametric extensions of
the Hammett equation for describing the ortho effect, the
intercept term often deviates from the value for the unsubstituted
compound, which notionally corresponds to hydrogen as an
ortho substituent.
FIGURE 2. Dependence of parameters λo/p (full line) and λp/m (dashed
line) on distance d defined in Scheme 2, according to eqs 28 and 15,
respectively.
By addressing the latter awkward and puzzling aspect of the
ortho effect from the viewpoint of the ISeR, we will argue that
the parent compound does not belong to the series of ortho-
substituted reactants. However, as noted in the context of eq
27, some features of the substituent hydrogen apparently fit into
the framework we have developed for the OPR. Thus, its
selectivity would be nil at all temperatures so that it could be
described by eq 24 as the isoselective substituent in the series.
The situation is very different when focusing on the linear
relationships between ortho and para activation parameters. It
is our contention that the isoselective substituent, denoted as
ISS, should be characterized in terms of parameters that conform
to eqs 16 and 19. Equating ∆qH°ortho-ISS ) ∆qH°para-ISS
()∆qH°ISS), eq 16 in conjunction with Table 3 for the chlorina-
tion of 2-phenoxypropanoic acids, gives ∆qH°ISS ) hR/(1 - R)
) 94.9 kJ mol-1. This high activation enthalpy for the
isoselective derivatives is marked in Figure 1. Similarly, from
∆qS°ortho-ISS ) ∆qS°para-ISS ()∆qS°ISS), eqs 19, 20, and 23,
together with the required numerical constants, we obtain ∆qS°SS
) sR/(1 - R) ) 10.6 J K-1 mol-1. At 298 K, these activation
performed for the parameter λp/m. The result of this exercise is
reported in Table 5 for some typical benzene derivatives and
other distances of interest.
The dependence of parameters λo/p and λp/m on distance d
can be visually appreciated in Figure 2, from which it is clear
that the effect of distance on λo/p is much more pronounced
than on λp/m. The lines describing these dependencies intersect
for the chemically interesting distance of 0.1463 nm, where λo/p
) λp/m. At distances greater than 0.2922 nm, there is a reversal
in the polar effect exerted by an ortho substituent in relation to
lower distances, or else when it is moved from the ortho to the
para position. These predicted opposite substituent effects add
to previously identified similar reversals.62,63 In this negative
region, parameter λo/p attains a minimum value of -0.565 at
the not too great distance of 1.300 nm and then increases slowly
up to the asymptotic limit of -0.500 at very great distances.
According to Table 5, nearly equal polar effects are expected
to arise from substituents in the ortho and para positions for
the protonation of aniline and the dissociation of phenol but
not for the dissociation of benzoic acid. From the slope of
theoretically calculated acidity of benzoic acids, Bo¨hm et al.51
estimated the ortho/para ratio of polar effects to be 0.81.
However, our electrostatic modeling for the benzoate ion
(65) Exner, O.; Bo¨hm, S. J. Phys. Org. Chem. 2006, 19, 393-401.
(66) Bowden, K.; Manser, G. E. Can. J. Chem. 1968, 46, 2941-2944.
(67) Aslam, M. H.; Burden, A. G.; Chapman, N. B.; Shorter, J.; Charton,
M. J. Chem. Soc., Perkin Trans. 2 1981, 500-508.
5334 J. Org. Chem., Vol. 72, No. 14, 2007

Chlorination of 2-Phenoxypropanoic Acid with NCP
parameters determine a rate constant kISS ) 0.8 × 10-9 dm3
mol-1 s-1, which indicates that the isoselective substituent would
exert a very retarding effect in relation to the parent substrate
for which kH ) 6.5 × 10-3 dm3 mol-1 s-1. In other words, this
value clearly shows that no isoselective substituent can possibly
be found for the present chlorination reaction. We conclude that,
in the analysis of the ortho effect, it is not appropriate to regard
a parent compound as both o-hydrogen and p-hydrogen deriva-
tives.
the same substituent. The corresponding isoselective temperature
is demonstrated to be equal to the isokinetic temperature. For
the present reaction series, the substrate containing the isos-
elective substituent is not the parent substrate, and this aspect
is viewed as an argument against using “substituent” o-hydrogen
in the correlation analysis of ortho substitution.
Experimental Section
Materials. All chemicals were reagent grade products. Substi-
tuted phenols and 2-chloropropanoic acid were the starting com-
pounds for the synthesis of the corresponding substituted 2-phe-
noxypropanoic acids using the procedure developed by Koelsch68
for obtaining 2-(monosubstituted phenoxy)acetic acids. This is
described for the parent substrate. A solution of sodium hydroxide
(20 g, 0.5 mol) in water (125 cm3) was added to 2-chloropropanoic
acid (54.2 g, 0.5 mol) in an ice bath, the temperature of the reacting
mixture being kept below 30 °C. To the resultant solution was added
a solution of phenol (47 g, 0.5 mol) in aqueous sodium hydroxide
(5 mol dm-3, 100 cm3). After heating the mixture for 20 h in a
steam bath, a good yield in sodium 2-phenoxypropanoate was
obtained. The reaction mixture was cooled, acidified to pH ) 2
with concentrated hydrochloric acid, and extracted several times
with diethyl ether. The combined organic extracts were then
extracted three times with 5% aqueous monosodium carbonate.
After removal of dissolved ether in a vacuum, the combined aqueous
extracts were acidified to pH ) 2 with concentrated hydrochloric
acid. The oily precipitate solidified to give the free acid. Substrates
were purified by repeated recrystallization from suitable solvents.
NCP was prepared by passing gaseous chlorine through a solution
of (R,S)-3-methyl-2,6-diphenylpiperidinium-4-one chloride in aque-
ous ethanol,3 recrystallized from ethanol, and dried in a vacuum
desiccator over calcium chloride. The purity of these reagents was
checked by determining their melting points. The purification of
solvents water and acetic acid is described elsewhere.2
Conclusions
The chlorination reaction of 2-phenoxypropanoic acid with
NCP was investigated in aqueous acetic acid at pH near 0.8.
Hence, for the first step of this reaction is proposed the
protonation of the chlorination agent according to eq 29, where
NCP is chemically denoted as >NCl.
>NCl + H+ {K
\
} >N+HCl
(29)
An IKR was found to hold approximately for a series of 20
reactions with various ortho and para substituents at five
different temperatures. From the corresponding isokinetic tem-
perature of 382 K, the preferential solvation of activated
complexes by water molecules is suggested. The effects of meta
and para substitution were well-described by the tetralinear
equation using Hammett σ constants, and this analysis indicated
a positively charged reaction center near the oxygen atom
belonging to the phenoxy group. Hence, for the second and rate-
determining step is proposed the electrophilic attack of the
protonated agent NCPH+ on the ether oxygen atom of the
substrate leading to the reversible formation of a chlorinated
cationic intermediate according to eq 30, where >NH stands
for 3-methyl-2,6-diphenylpiperidin-4-one.
Kinetic Measurements. Reactions were conducted in 50% (v/
v) acetic acid-water solvent containing perchloric acid (150 mmol
dm-3). Conditions of pseudo-first-order kinetics with respect to NCP
were implemented by using concentrations of 2-PPA 10- to 30-
fold the concentration of NCP. For the parent substrate at
k′
1
>N+HCl + XC6H4OCH(CH3)CO2H { } XC6H4O+ClCH
k-′ 1
(CH3)CO2H + >NH (30)
303.15 K, [NCP]0 ) 1 mmol dm-3 and [2-PPA]0 ) 30 mmol dm-3
.
Appropriate volumes of thermally equilibrate, separate reagent
solutions were poured into iodine flasks and glass-stoppered. The
temperature was kept constant within (0.01 °C. The rate of
disappearance of NCP was monitored by titration. Aliquots (5 cm3)
were withdrawn from the reaction flask at suitable time intervals,
quenched into a freshly prepared ice-cold aqueous solution made
up with potassium iodide (2% (w/w), 10 cm3) and sulfuric acid (5
mol dm-3, 10 cm3). Oxidation of iodide ions with the nonconsumed
NCP liberated molecular iodine, which was titrated using standard
sodium thiosulfate solution to a starch end point. Experimental rate
constants were obtained from the slope of least-squares linear fits
to the logarithmic first-order rate law, which gave high correlation
coefficients. Duplicate kinetic measurements were carried out for
all the experiments. Reported rate constants are average values with
an estimated reproducibility of 3% or better.
Product Analysis. The reaction products resulting from the
attack of NCP on 2-PPA were subjected to a detailed analysis. After
about 70% conversion, the reaction mixture from an actual kinetic
experiment was extracted with trichloromethane and shaken vigor-
ously with an equal volume of water. A white precipitate was
separated and shown to be 3-methyl-2,6-diphenylpiperidin-4-one
(or 3-methyl-2,6-diphenylazacyclohexan-4-one) by means of IR
spectrometry and mixed melting point determination. The liquid
extract was dried over anhydrous sodium sulfate and the organic
solvent removed under reduced pressure. The residue was monitored
For the third and last step in this mechanism, is proposed a
fast, irreversible chlorination of the phenolic ring according to
eq 31, where k′ . k-′ 1.
2
XC6H4O+ClCH(CH3)CO2H
9
k2′8 X(Cl)C6H3OCH
(CH3)CO2H + H+ (31)
Reported second-order rate constants k2 are then composite
quantities given by k2 ) k′K [H+], which explains the
1
experimentally observed acid-catalytic effect.
The actual chlorine position on the ring will depend on the
nature and position of substituent X in the substrate.
The ortho substitution effect was examined in terms of a novel
analysis using isokinetic activation enthalpies. A specific ortho
effect was detected for alkoxy substituents on the basis of large
differences between isokinetic and Eyring values for activation
enthalpies. Isokinetic activation enthalpies for ortho-substituted
substrates were found to be linearly correlated with those for
equally substituted substrates in the para position, the slope of
this straight line being probably related to the ortho/para ratio
of polar substituent effects. When an IKR holds for a reaction
series containing ortho and para isomers, it is shown that an
isoselective relationship also holds for the selectivity of a given
reactant toward the para- or ortho-substituted substrates with
(68) Koelsch, C. F. J. Am. Chem. Soc. 1931, 53, 304-305.
J. Org. Chem, Vol. 72, No. 14, 2007 5335

Segurado et al.
by thin-layer chromatograpy (TLC) on neutral alumina, along with
authentic samples of 2-PPA and its o-chloro and p-chloro deriva-
tives. The spots were eluted with a (4:5:1) butan-1-ol-water-acetic
acid mixture and developed by exposure to iodine vapor. The three
RF values measured for the residue matched exactly those of the
aforementioned authentic samples. This identification was further
confirmed by 13C NMR spectrometry of extracts of the TLC spots.
Computation. Least-squares and least-rectangles analyses were
performed. Calculation procedures using linear and nonlinear
regressions have been described in the context of the computer
programs used for solving a given equation. The method of least-
rectangles linear regression was used in the cases where both
variables are loaded with similar errors. Given the general straight
line y ) a + bx, best fitting parameters and their standard errors
can be computed from the related common linear regressions of y
on x, y ) a1 + b1x, and of x on y, x ) a2 + b2y. Slopes b1 and b2
have necessarily the same sign. Then slope b is given by their
geometric mean ((b1/b2)1/2, its sign being determined by the sign
common to b1 and b2. Alternatively and equivalently, the best slope
can be calculated as b ) (s(y)/s(x), where s(y) and s(x) are the
standard deviations obtained for the above common linear regres-
sions. Since the least-rectangles or orthogonal straight line must
go through the point defined by the mean-value coordinates (xj,yj),
then intercept a is computed as a ) yj - bxj. For a given set of
experimental data, an identical correlation coeficcient r is obtained
for the least-squares linear regressions of y on x and of x on y, and
therefore for the linear least-rectangles linear correlation between
x and y. Standard deviations of best fitting parameters, s(a) and
s(b), were estimated using the following equations,69,70 where n is
the number of data points and xj is the mean value of x.
s2(y)
s(a) )
(1 - r)[2 + xj(1 + r)/s2(x)]
x
n
b2(1 - r2)
s(b) )
x
n - 2
These calculations were implemented on a Microsoft Excel
spreadsheet using the LINEST function.
Acknowledgment. This work was supported in part by
Fundac¸a˜o para a Cieˆncia e a Tecnologia (Portugal).
(69) Tessier, G. Biometrics 1948, 4, 14-43.
(70) Kermack, K. A.; Haldane, J. B. S. Biometrika 1950, 37, 30-41.
JO0706224
5336 J. Org. Chem., Vol. 72, No. 14, 2007