Reparametrization and/or determination of hammett, inductive, mesomeric and aise substituent constants for five substituents: N+(CH 3)3, CH2N+(CH3) 3, CH2Py+, CH2SO2CH 3 and PO(OCH3)2

Article abstract of DOI:10.1135/cccc20042239

Ten meta- and para-substituted benzoic acids with substituants N ⁺(CH₃)₃, CH₂N⁺(CH ₃)₃, CH₂Py⁺, CH₂SO ₂CH₃ and PO(OCH₃)₂ were synthesized. Dissociation constants of these acids were determined in five solvents (water, ethanol, methanol, N,N-dimethylformamide, dimethyl sulfoxide) at 25°C. Dissociation constants of benzoic acid derivatives with other substituents H, CH₃, NHCOCH₃, OCH₃, F, Cl, Br, I, COCH ₃, CN, NO₂, SO₂CH₃ were taken from the literature (calibration set). Substituent constants σ_m, σ_p, σ_I, σ_R, and σⁱ for substituents N⁺(CH₃)₃, CH₂N⁺(CH₃)₃, CH₂Py ⁺, CH₂SO₂CH₃, and PO(OCH ₃)₂ were calculated by non-linear and PLS (partial least-square method with latent variables) calibration in three correlation models using the calibration set. Nonlinear regression appears more suitable and more universal than PLS calibration. The advantage of nonlinear regression is its independence on possibly missing data in the given solvent, evaluation of precision (standard deviation), the accessibility of necessary software, and easy calculation. However, in contrast to PLS calibration, this procedure fails in calculation of substituent constants with description of properties of substituents (substituent constants σ_I, σ_R). The obtained values of substituent constants are in good agreement with those published in the literature.

Full text of DOI:10.1135/cccc20042239

Reparametrization and/or Determination of Substituent Constants
2239
REPARAMETRIZATION AND/ OR DETERMINATION OF HAMMETT,
INDUCTIVE, MESOMERIC AND AISE SUBSTITUENT CONSTANTS
FOR FIVE SUBSTITUENTS: N+(CH3)3, CH2N+(CH3)3, CH2Py+,
CH2SO2CH3 AND PO(OCH3)2
b1
Jan PÍCHAa1, Radek CIBULKAa2,*, František LIŠKAa3, Patrik PAŘÍK and
b2
Oldřich PYTELA
a
Department of Organic Chemistry, Institute of Chemical Technology, Prague,
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: honzapicha@seznam.cz,
cibulkar@vscht.cz, liskaf@vscht.cz
Department of Organic Chemistry, University of Pardubice, 532 10 Pardubice, Czech Republic;
e-mail: patrik.parik@upce.cz, oldrich.pytela@upce.cz
1
2
3
b
1
2
Received May 17, 2004
Accepted July 2, 2004
This work is dedicated to Professor Otto Exner on the occasion of his 80th birthday.
Ten meta- an d para-substituted ben zoic acids with substituen ts N+(CH3)3, CH2N+(CH3)3,
CH2Py+, CH2SO2CH3 an d PO(OCH3)2 were syn th esized. Dissociation con stan ts of th ese acids
were determ in ed in five solven ts (water, eth an ol, m eth an ol, N,N-dim eth ylform am ide,
dim eth yl sulfoxide) at 25 °C. Dissociation con stan ts of ben zoic acid derivatives with oth er
substituen ts H, CH3, NHCOCH3, OCH3, F, Cl, Br, I, COCH3, CN, NO2, SO2CH3 were taken
from th e literature (calibration set). Substituen t con stan ts σm , σp, σI, σR, an d σi for substitu-
en ts N+(CH3)3, CH2N+(CH3)3, CH2Py+, CH2SO2CH3, an d PO(OCH3)2 were calculated by n on -
lin ear an d PLS (partial least-square m eth od with laten t variables) calibration in th ree correla-
tion m odels usin g th e calibration set. Non lin ear regression appears m ore suitable an d m ore
un iversal th an PLS calibration . Th e advan tage of n on lin ear regression is its in depen den ce on
possibly m issin g data in th e given solven t, evaluation of precision (stan dard deviation ), th e
accessibility of n ecessary software, an d easy calculation . However, in con trast to PLS calibra-
tion , th is procedure fails in calculation of substituen t con stan ts with description of proper-
ties of substituen ts (substituen t con stan ts σI, σR). Th e obtain ed values of substituen t con -
stan ts are in good agreem en t with th ose publish ed in th e literature.
Keyw ord s: Dissociation con stan ts; Ben zoic acid; Substituen t effects; Ham m ett equation ;
AISE; Quatern ary am m on ium salts; Sulfon es; Ph osph on ates.
Substituen t effects are still th e subject of in vestigation as well as a n ecessary
tool for study of m ech an ism s of organ ic reaction s. In recen t decades, origi-
n al Ham m ett con cept1,2 was exten ded an d com pleted by furth er approa-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)
doi:10.1135/cccc20042239

2240
Pícha, Cibulka, Liška, Pařík, Pytela:
ch es based on th e prin ciple of sim ilarity (e.g. lit.3–11). Correct evaluation of
substituen t con stan ts describin g properties of substituen ts is th e basic re-
quirem en t for application of th ese approach es. Old but so far im portan t
m eth ods are based on critical com pilation 12–14 of values obtain ed from ex-
perim en tal data; recen tly also a th eoretical approach h as been used15–21
.
Publish ed values of substituen t con stan ts of basic substituen ts sh ould be
con sidered to be valid. On th e oth er h an d, th is is n ot th e case of oth er sub-
stituen ts12–14. Th e reason for th is discrepan cy is a sm all n um ber of experi-
m en ts an d specificity of m odels or experim en tal con dition s used for deter-
m in ation of substituen t con stan ts (e.g. solven t). Th e evaluation of experi-
m en tal data is an oth er im portan t factor. It is suitable to apply m eth ods us-
in g large sets of experim en tal data obtain ed un der differen t con dition s.
Th is procedure allows extraction of th e effect of a substituen t as th e on ly
gen eral factor3,10,11 th us providin g m ore precise quan titative determ in ation
of substituen t con stan ts. Un reliable values of substituen t con stan ts can
cause in correct in terpretation of substituen t effects on ch em ical processes.
Th is work is focused on determ in ation or verification of th e values of
substituen t con stan ts σm , σp, σI, σR, an d σi (see lit.10,11) for substituen ts
N+(CH3)3, CH2N+(CH3)3, CH2Py+, CH2SO2CH3, an d PO(OCH3)2. Th is series
represen ts less com m on substituen ts with in terestin g properties.
PO(OCH3)2 is ph osph orus an alog of alkoxycarbon yl group. Substituen ts
N+(CH3)3, CH2N+(CH3)3, CH2Py+, an d CH2SO2CH3 h ave n o π electron s at
th e con n ectin g atom an d th ey could exten d class of substituen ts with on ly
in ductive effect on reaction cen ter. Num ber of substituen ts from th is class
with kn own substituen t con stan ts is still lim ited on alkyl or trifluorom eth yl
groups. In our case, we h ave m et th e problem of m issin g substituen t con -
stan ts of above m en tion ed substituen ts or th eir in accuracy durin g studies
of m ech an ism an d substituen t effect in th e case of cleavage of alkan oates
by oxim es22. Oxim e group represen ts after deproton ation powerful n ucleo-
ph ile readily attackin g th e ester fun ction 23,24; pyridin ium oxim es (e.g.
2-(h ydroxyim in om eth yl)-1-m eth ylpyridin ium iodide – 2-PAM) are used
an d studied as reactivators of ph osph orylated acetylch olin esterase poison ed
by organ oph osph orus in h ibitors23,25 or agen ts for h ydrolysis of toxic
organ oph osph ates an d ph osph on ates26,27. In th e presen ted series, substi-
tuen t con stan ts σm , σp, σI, σR for substituen ts N+(CH3)3, CH2 N+(CH3)3, an d
PO(OCH3)2 (lit.12–14 an d referen ces cited th erein , lit.28–30) are kn own . Th e
values for CH2Py+ an d CH2SO2CH3 an d th ose of substituen t con stan ts σi for
all th e above-m en tion ed substituen ts h ave n ot been publish ed. Th e secon d
purpose of th is work is verification of applicability of m ath em atic an d sta-
tistic m eth ods based on n on lin ear regression (NLR) an d PLS calibration 31
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
2241
(PLSC) for adjustm en t of substituen t con stan ts from large sets of experi-
m en tal data.
EXPERIMENTAL
Tem perature data were n ot corrected. TLC an alyses were carried out on a Kieselgel 60 F254
(Merck Laboratory Ch em icals). Colum n ch rom atograph y was perform ed on a Kieselgel 60 H
(Merck Laboratory Ch em icals). 1H NMR spectra were recorded on a Varian Gem in i 300 at
300.08 MHz. Ch em ical sh ifts are reported in ppm relative to tetram eth ylsilan e as an in tern al
stan dard, couplin g con stan ts (J) are given in Hz. Elem en tal an alyses (C, H, N) were per-
form ed on a Perkin –Elm er 240 an alyser.
Ch em icals
3-Meth ylben zoic acid, 4-(brom om eth yl)ben zoic acid, m eth yl 3-m eth ylben zoate, m eth yl
4-(brom om eth yl)ben zoate, eth yl 3-brom oben zoate, eth yl 4-iodoben zoate, an d diben zoyl
peroxide were obtain ed from Aldrich , sodium m eth an eth iolate, N-brom osuccin im ide,
4-(dim eth ylam in o)ben zoic acid, 3-(dim eth ylam in o)ben zoic acid, m eth yl iodide, an h ydrous
n ickel ch loride, an d trim eth yl ph osph ite were obtain ed from Fluka.
3-(Bromomethyl)benzoic acid (1). 3-Meth ylben zoic acid (10 g, 73.4 m m ol), N-brom osuccin -
im ide (13 g, 73.4 m m ol) an d diben zoyl peroxide (1.78 g, 7.3 m m ol) were dissolved in
200 m l an h ydrous tetrach lorom eth an e. Th e reaction m ixture was refluxed for 5 h , cooled
an d th e rem ain in g succin im ide was filtered off. Th e solven t was evaporated an d th e crude
product was purified by crystallization . Yield 6.85 g (63%), m .p. 150–154 °C (CCl4) (lit.32
154–155 °C). 1H NMR (DMSO-d6): 4.77 s, 2 H (CH2Br); 7.49 dd, 1 H, J(5,6) = J(5,4) = 7.7
(H-5); 7.68 d, 1 H, J(4,5) = 7.4 (H-4); 7.86 d, 1 H, J(6,5) = 7.7 (H-6); 8.01 s, 1 H (H-2).
Gen eral Procedure for Preparation of 2a an d 2b
Com poun d 1 (2 g, 9.3 m m ol) or 4-(brom om eth yl)ben zoic acid (2 g, 9.3 m m ol) was dissolved
in 50 m l of saturated solution of trim eth ylam in e in aceton e. Th e reaction m ixture was
stirred at am bien t tem perature for 1 h . Precipitated crystals were filtered off an d purified by
crystallization .
(3-Carboxybenzyl)trimethylammonium bromide (2a). Yield 1.42 g (56%), m .p. 216–218 °C
(m eth an ol–eth er). For C11H16BrNO2·H2O (292.2) calculated: 45.22% C, 6.21% H, 27.35% Br,
4.79% N; foun d: 44.98% C, 6.36% H, 27.18% Br, 4.76% N. 1H NMR (DMSO-d6): 3.07 s, 9 H
(N+(CH3)3); 4.69 s, 2 H (CH2N+); 7.62 dd, 1 H, J(5,4) = J(5,6) = 7.7 (H-5); 7.79 d, 1 H, J(4,5) =
6.6 (H-6); 8.05 d, 1 H, J(6,5) = 7.7 (H-4); 8.09 s, 1 H (H-2).
(4-Carboxybenzyl)trimethylammonium bromide (2b). Yield 1.61 g (63%), m .p. 242–246 °C
(m eth an ol–eth er). For C11H16BrNO2·0.5H2O (291.2) calculated: 45.38% C, 5.89% H, 27.44% Br,
4.81% N; foun d: 45.10% C, 6.13% H, 27.28% Br, 4.85% N. 1H NMR (DMSO-d6): 3.06 s, 9 H
(N+(CH3)3)); 4.66 s, 2 H (CH2N+); 7.66 d, 2 H, J(2,3) = J(6,5) = 7.9 (H-2, H-6); 8.01 d, 2 H,
J(3,2) = J(5,6) = 8.3 (H-3, H-5).
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2242
Pícha, Cibulka, Liška, Pařík, Pytela:
Gen eral Procedure for Preparation of 3a an d 3b (lit.33
)
Com poun d 1 (2 g, 9.3 m m ol) or 4-(brom om eth yl)ben zoic acid (2 g, 9.3 m m ol) an d pyridin e
(4 g, 25.3 m m ol) were dissolved in 50 m l aceton e. Th e reaction m ixture was stirred at am bi-
en t tem perature for 1 h , precipitated crystals were filtered off an d purified by crystallization .
N-(3-Carboxybenzyl)pyridinium bromide (3a). Yield 0.61 g (56%), m .p. 172–173 °C (eth an ol).
For C13H12BrNO2 (294.2) calculated: 53.08% C, 4.11% H, 27.16% Br, 4.76% N; foun d:
52.94% C, 4.17% H, 27.29% Br, 4.60% N. 1H NMR (DMSO-d6): 6.05 s, 2 H (CH2N+); 7.55 dd,
1 H, J(5,6) = J(5,4) = 7.6 (H-5); 7.85 d, 1 H, J(6,5) = 7.3 (H-6); 7.94 d, 1 H, J(4,5) = 7.6 (H-4);
8.13 s, 1 H (H-2); 8.20 dd, 2 H, J(5′,6′) = J(3′,2′) = 6.9 (H-3′, H-5′); 8.66 dd, 1 H, J(4′,5′) =
J(4′,3′) = 7.4 (H-4′); 9.36 d, 2 H, J(6′,5′) = J(2′,3′) = 5.6 (H-2′, H-6′).
N-(4-Carboxybenzyl)pyridinium bromide (3b). Yield 0.85 g (68%), m .p. 254–258 °C (eth an ol)
(lit.27 258 °C). 1H NMR (DMSO-d6): 6.02 s, 2 H (CH2N+); 7.63 d, 2 H, J(2,3) = J(6,5) = 8.3
(H-2, H-6); 7.95 d, 2 H, J(3,2) = J(5,6) = 8.3 (H-3, H-5); 8.20 dd, 2 H, J(5′,6′) = J(3′,2′) = 6.6
(H-3′, H-5′); 8.65 dd, 1 H, J(4′,5′) = J(4′,3′) = 7.7 (H-4′); 9.29 d, 2 H, J(6′,5′) = J(3′,2′) = 5.8
(H-2′, H-6′).
Gen eral Procedure for Preparation of 4a an d 4b (lit.34
)
4-(Dim eth ylam in o)ben zoic acid (3 g, 18 m m ol) or 3-(dim eth ylam in o)ben zoic acid (3 g,
18 m m ol) an d m eth yl iodide (7.66 g, 54 m m ol) were dissolved in 50 m l of m eth an ol an d
refluxed for 16 h . Th e solven t was evaporated an d th e crude product was purified by crystal-
lization .
(3-Carboxyphenyl)trimethylammonium iodide (4a). Yield 3.05 g (55%), m .p. 188–192 °C
(eth an ol) (lit.34 258 °C). For C10H14INO2 (307.1) calculated: 39.11% C, 4.59% H, 41.32% I,
4.56% N; foun d: 39.36% C, 4.51% H, 41.27% I, 4.46% N. 1H NMR (DMSO-d6): 3.64 s, 9 H
(N+(CH3)3); 7.75 dd, 1 H, J(5,6) = J(5,4) = 7.9 (H-5); 8.08 d, 1 H, J(4,5) = 7.7 (H-4); 8.25 d,
1 H, J(6,5) = 8.5 (H-6); 8.36 s, 1 H (H-2).
(4-Carboxyphenyl)trimethylammonium iodide (4b ). Yield 1.95 g (35%), m .p. 212–215 °C
(eth an ol) (lit.35 238 °C). For C10H14INO2 (307.1) calculated: 39.11% C, 4.59% H, 41.32% I,
4.56% N; foun d: 39.12% C, 4.80% H, 41.43% I, 4.41% N. 1H NMR (DMSO-d6): 4.64 s, 9 H
(N+(CH3)3); 7.79 d, 2 H, J(3,2) = J(5,6) = 9.1 (H-3, H-5); 8.01 d, 2 H, J(2,3) = J(6,5) = 9.1 (H-2,
H-6).
Meth yl 3-(Brom om eth yl)ben zoate (5) (lit.36
)
Meth yl 3-m eth ylben zoate (12 g, 79.9 m m ol), N-brom osuccin im ide (14.22 g, 79.9 m m ol) an d
diben zoyl peroxide (1.78 g, 7.3 m m ol) were dissolved in 200 m l dried tetrach lorom eth an e.
Th e reaction m ixture was refluxed for 5 h , cooled an d th e rem ain in g succin im ide was fil-
tered off. Th e solven t was evaporated an d th e crude product was purified by distillation un -
der reduced pressure. Yield 10.2 g (56%), b.p.104 °C/27 Pa–106 °C/27 Pa (lit.37 98 °C/27 Pa–
102 °C/27 Pa) 1H NMR (CDCl3): 3.92 s, 3 H (OCH3); 4.52 s, 2 H (CH2Br); 7.42 dd, 1 H,
J(5,6) = J(5,4) = 7.7 (H-5); 7.59 d, 1 H, J(4,5) = 7.7 (H-4); 7.95 d, 1 H, J(6,5) = 7.7 (H-6);
8.06 s, 1 H (H-2).
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
Gen eral Procedure for Preparation of 6a an d 6b (lit.38
2243
)
To a solution of sodium m eth an eth iolate (1.8 g, 25 m m ol) in 50 m l of dried DMF cooled to
0 °C, com poun d 5 (5.5 g, 24 m m ol) or m eth yl 4-(brom om eth yl)ben zoate (5.5 g, 24 m m ol)
was added an d th e reaction m ixture was stirred at am bien t tem perature for 24 h . Th e reac-
tion m ixture was poured in to 250 m l of water an d extracted with eth yl acetate (3 × 50 m l).
Th e com bin ed organ ic layers were wash ed with water (2 × 100 m l) an d dried with an h y-
drous m agn esium sulfate. Th e solven t was evaporated an d th e crude product was purified by
distillation un der reduced pressure.
Methyl 3-[(methylsulfanyl)methyl]benzoate (6a). Yield 2.05 g (44%), b.p. 98 °C/119 Pa–
100 °C/119 Pa. For C10H12O2S (196.1) calculated: 61.20% C, 6.16% H, 16.34% S; foun d:
60.98% C, 6.37% H, 16.24% S. 1H NMR (CDCl3): 1.98 s, 3 H (SCH3); 3.69 s, 2 H (CH2S);
3.91 s, 3 H (COOCH3); 7.39 dd, 1 H, J(5,4) = J(5,6) = 7.4 (H-5); 7.51 d, 1 H, J(4,5) = 7.4
(H-4); 7.92 d, 1 H, J(6,5) = 7.7 (H-6); 7.96 s, 1 H (H-2).
Methyl 4-[(methylsulfanyl)methyl]benzoate (6b ). Yield 3.1 g (72%), b.p. 115 °C/39 Pa–
119 °C/39 Pa (lit.32 122 °C/79 Pa–124 °C/79 Pa). 1H NMR (CDCl3): 1.97 s, 3 H (SCH3);
3.69 s, 2 H (CH2S); 3.90 s, 3 H (COOCH3); 7.37 d, 2 H, J(3,2) = J(5,6) = 7.9 (H-3, H-5);
7.98 d, 2 H, J(2,3) = J(6,5) = 8.2 (H-2, H-6).
Gen eral Procedure for Preparation of 7a an d 7b (lit.38
)
To a solution of 6a (1.8 g, 9 m m ol) or 6b (1.8 g, 9 m m ol) in 10 m l glacial acetic acid 5.2 m l
of 30% h ydrogen peroxide were added. Th e reaction m ixture was refluxed for 1 h an d th e
flask con ten ts were poured in to 100 m l cold water. Precipitated crystals were filtered off,
wash ed with water an d purified by crystallization .
Methyl 3-[(methylsulfonyl)methyl]benzoate (7a). Yield 1.52 g (73%), m .p. 120–121 °C (eth yl
acetate). For C10H12O4S (228.3) calculated: 52.62% C, 5.30% H, 14.05% S; foun d: 52.57% C,
5.56% H, 13.86% S. 1HNMR (DMSO-d6): 2.12 s, 3 H (SO2CH3); 3.93 s, 3 H (COOCH3); 4.29 s,
2 H (CH2SO2); 7.51 dd, 1 H, J(5,4) = J(5,6) = 7.7 (H-5); 7.66 d, 1 H, J(4,5) = 7.4 (H-4); 8.07 m ,
2 H (H-2, H-6).
Methyl 4-[(methylsulfonyl)methyl]benzoate (7b). Yield 1.44 g (69%), m .p. 161–163 °C (eth yl
acetate) (lit.38 162–164°C). 1H NMR (DMSO-d6): 2.78 s,
3 H (SO2CH3); 3.92 s, 3 H
(COOCH3); 4.30 s, 2 H (CH2SO2); 7.49 d, 2 H, J(3,2) = J(5,6) = 8.2 (H-3, H-5); 8.06 d, 2 H,
J(2,3) = J(6,5) = 7.9 (H-2, H-6).
Gen eral Procedure for Preparation of 8a an d 8b (lit.38
)
Ester 7a (1.04 g, 4.6 m m ol) or 7b (1.04 g, 4.6 m m ol) dissolved in 25 m l of eth an ol was
added to 10 m l 1 M sodium h ydroxide. Th e reaction m ixture was stirred at am bien t tem pera-
ture for 3 h . Eth an ol was evaporated an d pH was adjusted to 1 usin g 1 M h ydroch loric acid.
Th e resultin g precipitate was collected by filtration , wash ed with cold water an d purified by
crystallization .
3-[(Methylsulfonyl)methyl]benzoic acid (8a). Yield 0.61 g (63%), m .p. 214–217 °C (eth an ol).
For C10H12O4S (214.0) calculated: 50.46% C, 4.70% H, 14.97% S; foun d: 50.19% C, 4.87% H,
14.69% S. 1H NMR (DMSO-d6): 2.91 s, 3 H (SO2CH3); 4.59 s, 2 H (CH2SO2); 7.52 dd, 1 H,
J(5,4) = J(5,6) = 7.4 (H-5); 7.63 d, 1 H, J(4,5) = 7.4 (H-4); 7.93 d, 1 H, J(6,5) = 7.7 (H-6);
7.99 s, 1 H (H-2).
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2244
Pícha, Cibulka, Liška, Pařík, Pytela:
4-[(Methylsulfonyl)methyl]benzoic acid (8b). Yield 0.69 g (71%), m .p. 250–254 °C (eth an ol)
(lit.38 249–253 °C ). 1H NMR (DMSO-d6): 2.91 s, 3 H (SO2CH3); 4.57 s, 2 H (CH2SO2); 7.52 d,
2 H, J(3,2) = J(5,6) = 8.3 (H-3, H-5); 7.95 d, 2 H, J(2,3) = J(6,5) = 8.2 (H-2, H-6).
Gen eral Procedure for Preparation of 9a an d 9b (lit.39
)
To a stirred suspen sion of an h ydrous n ickel ch loride (0.16 g, 1.3 m m ol) in eth yl 3-brom o-
ben zoate (5.81 g, 25.3 m m ol) or eth yl 4-iodoben zoate (6.98 g, 25.3 m m ol) trim eth yl ph os-
ph ite (3.62 g, 29.2 m m ol) at 150 °C was dropped. Th e reaction m ixture was h eated for 1 h ,
cooled an d th en pure products were obtain ed by colum n ch rom atograph y (dich lorom eth an e–
m eth an ol, 100:2)
Ethyl 3-(dimethoxyphosphoryl)benzoate (9a). Yield 3.9 g (60%). For C11H15O5P (258.2) calcu-
lated: 51.17% C, 5.86% H, 12.00% P; foun d: 50.93% C, 5.93% H, 11.82% P. 1H NMR
3
(CDCl3): 1.29 t, 3 H, J(2′,1′) = 7.1 (OCH2CH3); 3.67 d, 6 H, JHP = 11.1 (OCH3); 4.28 q, 2 H,
J(1′,2′) = 7.0 (OCH2CH3); 7.46 m , 1 H (H-5); 7.87 ddt, 1 H, JHP = 12.9, J(4,5) = 7.6, J(4,2) =
J(4,6) = 1.3 (H-4); 8.12 dd, J(6,5) = 7.6, JHP = J(6,2) = J(4,2) = 1.2 (H-6); 8.34 d, 1 H, JHP
=
12.9 (H-2).
Ethyl 4-(dimethoxyphosphoryl)benzoate (9b). Yield 4.62 g (71%). For C11H15O5P (258.2) cal-
culated: 51.17% C, 5.86% H, 12.00% P; foun d: 50.09% C, 5.94% H, 11.91% P. 1H NMR
3
(CDCl3): 1.36 t, 3 H, J(2′,1′) = 7.1 (OCH2CH3); 3.74 d, 6 H, JHP = 12.9 (OCH3); 4.21 q, 2 H,
3
J(1′,2′) = 7.0 (OCH2CH3); 7.84 dd, 2 H, JHP = 12.9, J(3,2) = J(5,6) = 8.3 (H-3, H-5); 8.09 dd,
4
2 H, JHP = 3.8, J(2,6) = J(3,5) = 8.3 (H-2, H-6).
Gen eral Procedure for Preparation of 10a an d 10b (lit.40
)
To ester 9a (1.5 g, 5.8 m m ol) or 9b (1.5 g, 5.8 m m ol) dissolved in 25 m l eth an ol sodium h y-
droxide (0.23 g, 5.8 m m ol) in 10 m l water was added. Th e reaction m ixture was stirred at
am bien t tem perature for on e week, eth an ol was evaporated an d pH was adjusted to 1 usin g
0.01 M h ydroch loric acid. Th e separated oil was extracted with ben zen e (3 × 20 m l) an d
com bin ed organ ic layers were dried with an h ydrous m agn esium sulfate. Th e solven t was
evaporated an d crude products were purified by crystallization .
3-(Dimethoxyphosphoryl)benzoic acid (10a). Yield 0.46 g (34%), m .p. 122–124 °C (ben zen e,
3
petroleum eth er) (lit.41 124.5–125.5 °C). 1H NMR (DMSO-d6): 3.63 d, 6 H, JHP = 11.1 (OCH3);
7.67 m , 1 H (H-5); 7.92 dd, 1 H, JHP = 12.6, J(4,5) = 7.6 (H-4); 8.19 m , 2 H (H-2, H-6).
4-(Dimethoxyphosphoryl)benzoic acid (10b). Yield 0.65 g (49%), m .p. 115–118 °C (ben zen e,
3
petroleum eth er) (lit.41 116–117 °C). 1H NMR (DMSO-d6): 3.74 d, 6 H, JHP = 11.1 (OCH3);
3
4
7.91 dd, 2 H, JHP = 13.2, J(3,2) = J(5,6) = 8.5 (H-3, H-5); 8.19 dd, 2 H, JHP = 3.8, J(2,6) =
J(3,5) = 8.3 (H-2, H-6).
Determ in ation of Dissociation Con stan ts
Dissociation con stan ts of com poun ds 2–4, 8, an d 10 (as pKa) at 25 °C in water (W), m eth a-
n ol (MeOH), eth an ol (EtOH), N,N-dim eth ylform am ide (DMF), an d dim eth yl sufoxide
(DMSO) were determ in ed by poten tiom etric titration usin g an autom atic titrator Titralab 3
(Radiom eter) un der th e sam e experim en tal con dition s an d usin g th e sam e electrodes as in
previous works42–44
.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
2245
Calculation of Substituen t Con stan ts
Procedures used were based on th e prediction of un kn own substituen t con stan ts by m ean s of
correlation relation s between logarith m of dissociation con stan ts meta- an d para-substituted
ben zoic acids in selected solven ts (water, m eth an ol, eth an ol, N,N-dim eth ylform am ide,
dim eth yl sulfoxide) an d kn own substituen t con stan ts. Th e calibration set of substituen ts
with kn own an d valid substituen t con stan ts in cluded H, CH3, NHCOCH3, OCH3, F, Cl, Br, I,
COCH3, CN, NO2, SO2CH3. Th e substituen ts were ch osen depen din g on accessibility of all
values of dissociation con stan ts of correspon din g meta- an d para-ben zoic acid derivatives in
relevan t solven ts. Th e values of dissociation con stan ts were taken from th e literature8,45,46
.
Substituen t con stan ts for group of substituen ts N+(CH3)3, CH2N+(CH3)3, CH2Py+, CH2SO2CH3,
an d PO(OCH3)2 were evaluated usin g th e procedures described below.
Equation (1) was used for prediction of Ham m ett substituen t con stan ts σm an d σp by
n on lin ear regression
log Kjk = log K0,j + ρj σk
,
(1)
wh ere in dexes j an d k are th e n um ber of solven t used for m easurem en t of dissociation con -
stan ts an d th e n um ber of substituen t (n um bered in depen den tly in position meta an d para),
respectively. Values of log Kjk are logarith m s of experim en tal values of dissociation con stan ts
of subtituted ben zoic acid derivatives in a given solven t, log K0,j values are un kn own in ter-
cepts, ρj are un kn own reaction con stan ts in th e Ham m ett equation for given solven t, an d σk
are Ham m ett substituen t con stan ts. Un kn own param eters in Eq. (1) were optim ized m in i-
m izin g th e sum of squares S usin g Eq. (2).
exp
jk
pred 2
jk
S = (log K − log K
)
= m in
(2)
∑
jk
An alogously to th e previous case, Eq. (3) was used for prediction of substituen t con stan ts σI
an d σR by n on lin ear regression .
log Kjk = log K0,j + ρI,j σI,k + ρR,j σR,k
,
(3)
wh ere ρI,j an d ρR,j are reaction con stan ts (th e sam e m ean in g of sym bols as in Eq. (1)). Opti-
m ization was m ade by m in im ization of th e fun ction S in Eq. (2).
For prediction of substituen t con stan ts σi accordin g to AISE (lit.10,11) by n on lin ear regres-
sion , Eq. (4) was applied.
log Kjk = log K0,j + ρI,j δI,k (σ ik − σ i0 ) + ρN,j δN,k (σ ki − σ 0i ) + ρE,j δE,k (σ ki − σ 0i ) ,
(4)
wh ere ρI,j, ρN,j, an d ρE,j are reaction con stan ts, sym bols δ are m ultiplyin g con stan ts wh ich
assum e th e values 1 or 0 depen din g on th e type of in teraction of substituen t with reaction
cen ter (I, substituen ts with in ductive effect on ly; N, in tern al n ucleoph iles; E, in tern al ele-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2246
Pícha, Cibulka, Liška, Pařík, Pytela:
ctroph iles), an d σ 0i is an un kn own param eter in th e AISE th eory. Th e m ean in g of sym bols is
th e sam e as in Eq. (1). Optim ization was m ade by m in im ization of th e fun ction S in Eq. (2).
For prediction of substituen t con stan ts by PLS calibration 31, decom position of m atrixes X
an d Y in th e first step was realized usin g Eqs (5) an d (6)
X = TPT + E ,
Y = UQT + F ,
(5)
(6)
with defin ed relation between m atrixes T an d U:
U = TA + H .
(7)
In Eqs (5)–(7), X is th e m atrix of log Ka values (calibration set of substituen ts, in rows are
substituen ts, in colum n s are solven ts used in th e m easurem en ts), Y m ean s th e m atrix of
substituen t con stan ts (rows represen t substituen ts, two colum n s represen t a pair of kn own
Ham m ett substituen t con stan ts σm , σp or a pair of kn own substituen t con stan ts σI, σR),
T an d U are m atrixes of laten t variables (score), A is th e diagon al m atrix describin g relation
between laten t variables, P an d Q are loadin g m atrixes; rem ain in g sym bols are residual m a-
trixes.
Matrix Yc (in rows are substituen ts, two colum n s represen t a pair of un kn own Ham m ett
substituen t con stan ts σm , σp or a pair of un kn own substituen t con stan ts σI, σR) was calcu-
lated usin g Eq. (8) with calculated m atrixes P, A an d Q, an d m atrix Xc of m easured values
of log Ka (in rows are substituen ts N+(CH3)3, CH2N+(CH3)3, CH2Py+, CH2SO2CH3, an d
PO(OCH3)2, in colum n s are solven ts used in m easurem en ts).
Yc = [(PTP)–1PT(Xc)T]TAQT.
(8)
All calculation s were carried out usin g stan dard algorith m s31 an d th e own OPstat program .
RESULTS AND DISCUSSION
Syntheses and Acidity of Substituted Benzoic Acids
For determ in ation of substituen t con stan ts, 3- an d 4-substituted ben zoic ac-
ids 2–4, 8, an d 10 were syn th esized. Quatern ary salts 2 an d 3 were prepared
by reaction of correspon din g (brom om eth yl)ben zoic acids with trim eth yl-
am in e or pyridin e, an ilin ium salts 4 by quatern ization of (dim eth ylam in o)-
ben zoic acids with m eth yl iodide. Com poun ds 8 were syn th esized startin g
from correspon din g m eth yl (brom om eth yl)ben zoate by substitution with
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
2247
sodium m eth an eth iolate followed by oxidation with h ydrogen peroxide
an d h ydrolysis of ester fun ction . Com poun ds 10 were prepared from eth yl
3-(brom om eth yl)ben zoate or eth yl 4-(iodom eth yl)ben zoate by reaction
with trim eth yl ph osph ite followed by h ydrolysis of carboxylate ester.
O
OH
O
OH
O
OH
CH2
Br
N
N(CH3)3
CH2N(CH3)3
Br
I
Position
Position
Position
3
4
3a
3b
3
4
4a
4b
3
4
2a
2b
O
OH
O
OH
PO(OCH3)2
CH2SO2CH3
Position
Position
3
4
10a
10b
3
4
8a
8b
Dissociation con stan ts (pKa) of ben zoic acids 2–4, 8, an d 10 were m ea-
sured in water, m eth an ol, eth an ol, N,N-dim eth ylform am ide, an d dim eth yl
sulfoxide. Th e obtain ed data are sum m arized in Table I.
Hammett Substituent Constants
Th e values of substituen t con stan ts σm an d σp given in Table II were ob-
tain ed usin g n on lin ear regression an d PLS calibration by th e procedures
described in Experim en tal. Com putation by n on lin ear regression fast con -
verged to m in im um th us givin g eviden ce about suitability of th e correla-
tion m odel. Th e residual stan dard deviation in n on lin ear regression accord-
in g to Eq. (1) calculated by Eq. (2) usin g residual sum of squares was s =
0.130 for a set of 174 experim en tal values of log Ka. Th is value is com para-
ble with obviously precision of poten tiom etric determ in ation of dissocia-
tion con stan ts in n on aqueous solven ts. Th erefore, m odel (1) can be con sid-
ered to be valid. In PLS calibration , two laten t variables in m atrix X (cali-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2248
Pícha, Cibulka, Liška, Pařík, Pytela:
bration set of log Ka values) explain ed 99.55% of overall variability an d all
variability in m atrix Y (values of substituen t con stan ts σm an d σp). Th us, ca-
libration can be con sidered to be good en ough for prediction of un kn own
substituen t con stan ts.
A com parison of calculated substituen t con stan ts with th ose obtain ed
by oth er m eth ods sh ows a very good agreem en t in th e scope of data pub-
lish ed in th e literature. Th e calculated Ham m ett substituen t con stan ts for
CH2SO2CH3 group are com parable with th ose for CH2SO2C6H5 (σm = 0.15,
σp = 0.17, lit.53). Sim ilarly, th e electron -with drawin g effect of CH2Py+ is
practically th e sam e as in th e case of CH2N+(CH3)3 keepin g in m in d accu-
racy of th e obtain ed results. Values of σp are com parable, with th e excep-
tion of PO(OCH3)2, with correspon din g values of σm sh owin g th e dom in at-
in g in fluen ce of th e in ductive effect.
Substituent Constants σI and σR
Substituen t con stan ts σI an d σR calculated by n on lin ear regression usin g
Eq. (3) sh ow h igh in tercorrelation (very slow con vergen ce of th e optim iza-
TABLE I
Mean values of pKa of substituted ben zoic acids an d th eir stan dard deviation s s (in paren -
th eses) calculated from th ree to eigh t repeated m easurem en ts in water (W), m eth an ol
(MeOH), eth an ol (EtOH), N,N-dim eth ylform am ide (DMF), an d dim eth yl sulfoxide (DMSO)
Solven t
Substituen t
W
MeOH
EtOH
DMF
DMSO
3-N+(CH3)3I–
4-N+(CH3)3I–
3-CH2N+(CH3)3Br–
4-CH2N+(CH3)3Br–
3-CH2Py+Br–
3.45 (0.05)
3.58 (0.04)
3.77 (0.06)
3.74 (0.04)
3.84 (0.06)
3.71 (0.03)
4.09 (0.04)
4.13 (0.05)
3.85 (0.06)
3.64 (0.06)
7.73 (0.03)
7.99 (0.03)
8.32 (0.07)
8.43 (0.08)
8.37 (0.02)
8.52 (0.10)
9.17 (0.06)
9.22 (0.07)
8.75 (0.05)
8.65 (0.04)
8.05 (0.01)
8.49 (0.01)
8.82 (0.06)
8.96 (0.08)
8.82 (0.08)
9.14 (0.03)
9.86 (0.04)
9.95 (0.06)
9.51 (0.01)
9.33 (0.04)
10.33 (0.08)
10.46 (0.09)
9.36 (0.09)
9.79 (0.08)
11.15 (0.11) 10.03 (0.14)
11.13 (0.09) 10.17 (0.09)
11.22 (0.10) 10.37 (0.08)
11.31 (0.07) 10.24 (0.11)
11.87 (0.04) 10.50 (0.09)
11.97 (0.04) 10.74 (0.08)
11.37 (0.10) 10.14 (0.07)
11.15 (0.05) 10.14 (0.04)
4-CH2Py+Br–
3-CH2SO2CH3
4-CH2SO2CH3
3-PO(OCH3)2
4-PO(OCH3)2
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
2249
tion process) probably due to th e way of settin g substituen t con stan ts σm
an d σp. For successful optim ization it was n ecessary (with th e exception of
substituen t PO(OCH3)2) to defin e value of substituen t con stan t σR = 0. Un -
der th is con dition , values of σI an d σR (Table III) were obtain ed usin g th e
procedure described in Experim en tal. Th ese values were obtain ed also by
PLS calibration (Table III). Sm all values of σR obtain ed by PLS calibration
con firm validity of th eir om ission in calculation s by n on lin ear regression .
Th e residual stan dard deviation in n on lin ear regression accordin g to
Eq. (1) calculated from Eq. (2) usin g residual sum of squares was s = 0.134
for th e set of 174 experim en tal values of dissociation con stan ts, con se-
TABLE II
Values of substituen t con stan ts σm an d σp obtain ed usin g Eq. (1) or PLS calibration by Eq. (8);
com parison with data from th e literature
σm
σp
Substituen t
N+(CH3)3
NLR
PLSC
Literature
NLR
PLSC
Literature
0.99 ± 0.05 0.97
0.99a (W)
0.89 ± 0.04 0.96
0.96a(W)
0.88b
0.82b
1.02c (50% EtOH)
0.88c (50% EtOH)
0.72d (W, log k)
0.98e (W)
1.03e (W)
1.02e (10% EtOH)
1.13e (50% EtOH)
1.23e (75% EtOH)
0.99f (W)
0.94e (10% EtOH)
0.99e (50% EtOH)
1.03e (75% EtOH)
0.96f (W)
0.88g
0.82g
CH2N+(CH3)3
0.61 ± 0.04 0.61
0.57 ± 0.04 0.61
0.44d (W, log k)
0.67e (W)
0.68e (W)
0.69e (10% EtOH)
0.82e (50% EtOH)
0.92e (75% EtOH)
0.40g
0.68e (10% EtOH)
0.73e (50% EtOH)
0.78e (75% EtOH)
0.44g
CH2Py+
0.55 ± 0.04 0.57
0.19 ± 0.04 0.20
0.41 ± 0.04 0.43
0.50 ± 0.04 0.54
0.10 ± 0.04 0.10
0.50 ± 0.04 0.49
CH2SO2CH3
PO(OCH3)2
0.42h (50% EtOH)
0.53h (50% EtOH)
0.34i
(
19F NMR)
0.43i 19F NMR)
(
a
b
c
d
e
f
g
h
i
Lit.47
,
lit.3, lit.48
,
lit.49
,
lit.30
,
lit.8, lit.13
,
lit.41
,
lit.50
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2250
Pícha, Cibulka, Liška, Pařík, Pytela:
quen tly sligh tly m ore h igh er th an in m odel (1). Th e explain ed variabilities
in PLS calibration were sim ilar to calculation accordin g to m odel (1). From
th ese fin din g results th e fact th at m odels (1) an d (3) are of th e sam e statisti-
cal sign ifican ce for in terpretation of experim en tal data. Differen ces be-
tween th e calculated substituen t con stan ts an d kn own values obtain ed by
oth er procedures (see Table III) are h igh er th an in th e case of Ham m ett con -
stan ts. Th at is in particular th e case of ch arged substituen t N+(CH3)3 an d
also PO(OCH3)2, wh ere th e m esom eric effect seem s to be un derestim ated.
Substituent Constant σi in AISE Theory
Due to n on -additive ch aracter of Eq. (4), on ly n on lin ear regression can
be used for settin g un kn own values of substituen t con stan t σi. Th e calcula-
tion con verged fast to a m in im um th us poin tin g to a suitable m odel with -
out in tercorrelation s between param eters. Th e calculated values σi for sub-
stituen ts are: N+(CH3)3 0.788 ± 0.035, CH2N+(CH3)3 0.501 ± 0.024, CH2Py+
0.450 ± 0.023, CH2SO2CH3 0.138 ± 0.025, an d PO(OCH3)2 0.407 ± 0.019;
residual stan dard deviation was s = 0.134 for a set of 174 experim en tal val-
ues of dissociation con stan ts.
TABLE III
Values of substituen t con stan ts σI an d σR obtain ed by n on lin ear regression usin g Eq. (3) an d
PLS calibration usin g Eq. (8); com parison with literature data
σI
σR
Substituen t
N+(CH3)3
NLR
PLSC
0.91
Literature
NLR
0a
PLSC
0.03
Literature
0.94 ± 0.03
0.73b
0.61, 0.59c
0.99d (NMR)
1.07e
–0.08d (NMR)
CH2N+(CH3)3
CH2Py+
0.60 ± 0.03
0.54 ± 0.03
0.18 ± 0.03
0.27 ± 0.08
0.54
0.53
0.22
0.31
0a
0a
0a
0.08
0.03
0.06
0.22
CH2SO2CH3
PO(OCH3)2
0.21f (IR)
0.35g
0.09f (IR)
0.18g
0.19h
0.26 ± 0.11
0.16d (NMR)
0.32e
0.06d (NMR)
0.17e
a
b
c
d
e
f
g
h
Arbitrary, lit.51
,
lit.30
,
lit.13
,
lit.8, lit.52
,
lit.41
,
lit.50
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Reparametrization and/or Determination of Substituent Constants
2251
Conclusion
Substituen t con stan ts σm , σp, σI, σR, an d σi for substituen ts N+(CH3)3,
CH2N+(CH3)3, CH2Py+, CH2SO2CH3, an d PO(OCH3)2 in th ree correlation
m odels were calculated by two differen t m ath em atical m eth ods usin g a
large set of experim en tal data an d calibration set. Th e predicted values of
substituen t con stan ts calculated by two m eth ods are practically in distin -
guish able. It was foun d th at n on lin ear regression is m ore suitable an d m ore
un iversal th an PLS calibration . Th e advan tages of n on lin ear regression are:
in depen den ce on variate experim en tal data from on e solven t, possibility of
estim ation of precision of substituen t con stan ts (stan dard deviation ), avail-
ability of software an d easy calculation . On th e oth er h an d, n on lin ear re-
gression fails for calculation of con stan ts with additive description of sub-
stituen ts (σI an d σR) in con trast to PLS calibration . Th e calculated values
correspon d with th ose cited for th e sam e substituen ts in th e literature.
Financial support for this work was provided by the Grant Agency of the Czech Republic (grant
No. 203/01/1093).
REFERENCES
1. Shorter J.: Chem. Listy 2000, 94, 210.
2. Hammett L. P.: Physical Organic Chemistry, 2nd ed. McGraw–Hill, New York 1970.
3. Swain C. G., Lupton E. C.: J. Am. Chem. Soc. 1968, 90, 4328.
4. Ehrenson S., Browlee R. T. C., Taft R. W.: Prog. Phys. Org. Chem. 1973, 10, 1.
5. Charton M.: Prog. Phys. Org. Chem. 1981, 13, 120.
6. Shorter J.: Correlation Analysis of Organic Reactivity. Wiley, Chichester 1982.
7. Taft R. W., Topsom R. D.: Prog. Phys. Org. Chem. 1987, 16, 1.
8. Exner O.: Correlation Analysis of Chemical Data. Plenum, New York 1988.
9. Shorter J. in: Similarity Models in Organic Chemistry, Biochemistry and Related Fields (R. I.
Zalewski., T. M. Krygowski and J. Shorter, Eds), Chap. 2. Elsevier, Amsterdam 1991.
10. Pytela O.: Collect. Czech. Chem. Commun. 1995, 60, 1502.
11. Pytela O.: Collect. Czech. Chem. Commun. 1996, 61, 704.
12. Exner O. in: Correlation Analysis in Chemistry, Recent Advances (N. B. Chapman and
J. Shorter, Eds), Chap. 10. Plenum Press, New York 1978.
13. Hansch C., Leo A., Taft R. W.: Chem. Rev. 1991, 91, 165.
14. Shorter J.: Pure Appl. Chem. 1994, 66, 2451.
15. Exner O., Ingr M., Čársky P.: J. Mol. Struct. (THEOCHEM) 1997, 397, 231.
16. Cherkasov A. R., Galkin V. I., Cherkasov R. A.: J. Phys. Org. Chem. 1998, 11, 437.
17. Kvasnička V., Sklenák Š., Pospíchal J.: J. Am. Chem. Soc. 1993, 115, 1496.
18. Exner O.: J. Phys. Org. Chem. 1999, 12, 265.
19. Galkin V. I.: J. Phys. Org. Chem. 1999, 12, 283.
20. Exner O., Böhm S.: J. Org. Chem. 2002, 67, 6320.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2252
Pícha, Cibulka, Liška, Pařík, Pytela:
21. Cherkasov A., Sprous D. G., Chen R.: J. Phys. Chem. A 2003, 107, 9695.
22. Pícha J., Cibulka R., Hampl F., Liška F., Pařík P., Pytela O.: Collect. Czech. Chem. Commun.
2004, 69, 397.
23. Terrier F., MacCormack P., Kizilian E., Hallé J. C., Demerseman P., Guir F., Lion C.:
J. Chem. Soc., Perkin Trans. 2 1991, 153.
24. Buncel E., Cannes C., Chratrousse A.-P., Terrier F.: J. Am. Chem. Soc. 2002, 124, 8766.
25. Dawson R. M.: J. Appl. Toxicol. 1994, 14, 317; and references therein.
26. Epstein J., Kaminski J. J., Bodor N., Enever R., Sowa J., Higuchi T.: J. Org. Chem. 1978,
43, 2816.
27. Cibulka R., Hampl F., Kotoučová H., Mazáč J., Liška F.: Collect. Czech. Chem. Commun.
2000, 65, 227.
28. Smith J. H., Meger F. M.: J. Org. Chem. 1969, 34, 77.
29. Hoefnagel A. J., Monshouwer J. C., Snorn E. C. G., Wepster B. M.: J. Am. Chem. Soc.
1973, 95, 5350.
30. Hoefnagel A. J., Hoefnagel M. A., Wepster B. M.: J. Org. Chem. 1978, 43, 4720.
31. Wold S., Geladi P., Esbensen K., Öhman J.: J. Chemom. 1987, 1, 41.
32. Litak P. T., Kauffman J. M.: J. Heterocycl. Chem. 1994, 31, 457.
33. Willems J., Nys J.: Bull. Soc. Chim. Belg. 1957, 66, 502.
34. Tadros W., Sakla A. B.: J. Chem. Soc. 1954, 1116.
35. Zaki A., Tadros W.: J. Chem. Soc. 1941, 562.
36. Dvorníkova V., Smithrud D. B.: J. Org. Chem. 2002, 67, 2160.
37. Turner F. A., Gearien J. E.: J. Org. Chem. 1959, 24, 1952.
38. Chand P., Babu Y. S., Bantia S., Chu. N., Cole L. B., Kotian P. L., Laver W. G.,
Montgomery J. A., Pathak V. P., Petty S. L., Shrout D. P., Walsh D. A., Walsh G. M.:
J. Med. Chem. 1997, 40, 4030.
39. Nagarajan K., Shelly K. P., Perkins R. R., Stewart R.: Can. J. Chem. 1987, 65, 1729.
40. Freedman L. D., Jaffe H. H.: J. Am. Chem. Soc. 1955, 77, 920.
41. Tsvetkov E. N., Lobanov D. I., Izosenkova L. A., Kabachnik M. I.: Zh. Obshch. Khim.
1969, 39, 2177.
42. Ludwig M., Pytela O., Kalfus K., Večeřa M.: Collect. Czech. Chem. Commun. 1984, 49,
1182.
43. Ludwig M., Pytela O., Večeřa M.: Collect. Czech. Chem. Commun. 1984, 49, 2593.
44. Ludwig M., Pytela O., Večeřa M.: Collect. Czech. Chem. Commun. 1986, 51, 1948.
45. Ludwig M., Baron V., Kalfus K., Pytela O., Večeřa M.: Collect. Czech. Chem. Commun.
1986, 51, 2135.
46. Pytela O., Prusek O.: Collect. Czech. Chem. Commun. 1999, 64, 1617.
47. Villi A. V.: Z. Phys. Chem. (Frankfurt) 1960, 26, 42.
48. Roberts J. D., Clement R. A., Drysdale J. J.: J. Am. Chem. Soc. 1951, 73, 2181.
49. Smith J. H., Meger F. M.: J. Org. Chem. 1969, 34, 77.
50. Prikoszovich W., Schindlbauer H.: Chem. Ber. 1969, 102, 2922.
51. Charton M.: J. Org. Chem. 1964, 29, 1222.
52. Katritzky A. R., Pinzelli R. F., Sinnott M. V., Topsom R. D.: J. Am. Chem. Soc. 1970, 92,
6861.
53. Exner O.: Collect. Czech. Chem. Commun. 1966, 31, 65.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)