Solvent and substituent effects on the thermolysis of antimalarial fluorophenyl substituted 1,2.4-trioxanes

Article abstract of DOI:10.3390/80900655

The kinetics and mechanism of the thermal decomposition reaction of cis-6-(4-fluoropheny1)-5,6-[2-(4-fluorophenyl)-propylidene]-3, 3-tetramethylene-1,2,4-trioxacyclo-hexane (I) were investigated separately in n-hexane and in methanol solutions over the te

Full text of DOI:10.3390/80900655

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Molecules 2003, 8, 655-662
molecules
ISSN 1420-3049
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Solvent and Substituent Effects on the Thermolysis of
Antimalarial Fluorophenyl Substituted 1,2.4-Trioxanes
Lazaro F. R. Cafferata* and Ruben S. Rimada
Laboratorio LADECOR (UNLP) and CINDECA (CONICET), Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, Calles 47 Y 115, (1900) La Plata, República
Argentina.
* Author to whom correspondence should be addressed: caferata@quimica.unlp.edu.ar
Received: 25 September 2002; in revised form: 18 July 2003/ Accepted: 20 July / Published: 15 August
2003
Abstract: The kinetics and mechanism of the thermal decomposition reaction of cis-6-(4-
fluoropheny1)-5,6-[2-(4-fluorophenyl)-propylidene]-3,3-tetramethylene-l,2,4-trioxacyclo-
hexane (I) were investigated separately in n-hexane and in methanol solutions over the
temperature and concentration ranges of 393.2-443.2 K and 2.7-54 x l0-5 M, respectively.
The values of the activation parameters for both reactions were compared with the
corresponding ones for the thermolysis of cis-6-(4-fluorophenyl-5,6-[2-(4-fluorophenyl)-
3-hydroxypropylidene]-3,3-tetramethylene-1,2,4-trioxacyclohexane (II), investigated in
the same solvents and temperature range. Substituent and solvent effects on the initial
homolytic rupture of the O-O peroxydic bonds of those molecules were evaluated.
Keywords: Peroxides – Thermolysis - Fluorophenyl Substituted 1,2,4-trioxanes -
Thermal decomposition Reactions - Solvent and Substituents Effects - Antimalarial
Compounds

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Introduction
Cyclic peroxides of the substituted 1,2,4-trioxane type are structurally related to the six-member
ring 1,2,4,5-tetroxanes and 1,2,4,5-trioxazines already investigated by kinetic methods [1,2]. Examples
of those compounds, which are available through new synthetic methods, are related to the antimalarial
activity of molecules with a 1,2,4-trioxane ring as in artemisinin and their derivatives [3]. Furthermore,
the activation parameters values for the unimolecular thermolysis of acyclic organic peroxides [4,5]
and cyclic diperoxides [6-8] depend significantly on the reaction media. On the other hand, mass
spectrometric evidence for the analysis of the products of thermolysis of other 1,2,4-trioxanes in
solution have been reported [9]. The kinetics of all the cases cited constitute genuine “reaction series”
[7] where the decomposition of those molecules is controlled by their O-O bond homolysis.
Herein, the kinetic data on the thermolysis of molecules I and II in methanol solution [10] is
compared with that obtained in n-hexane solution [11], to examine possible solvent effects in their
thermolyses.
F
F
OH
H
O
H
O
O
O
O
O
F
F
(I)
(II)
Results and Discussion
Rate measurements on the thermal decomposition reactions of I and II in n-hexane and methanol
solutions in the 10-4 - 10-5 M initial concentration and 393.2- 443.2 K temperature range show first-
order kinetic law behavior up to ca. 98% conversions of both trioxanes (Table I).
Table I. First-Order Rate Constant Values for the Thermal Decomposition
Reactions of Trioxanes I and II in n-Hexane and Methanol Solutions.
Temp
K
Reaction
Solvent
105 ·[I]a
105 ·kobs
s-1
105·[II]a
105·kobs
s-1
M
M
393.2
393.2
403.2
n-hexane
methanol
n-hexane
13.5
2.7
5.1 ± 0.5
38.2 ± 0.4
14 ± 1.5
82
1.05
82
2.7 ± 0.2
27.6 ± 3.0
4.2 ± 0.4
13.5

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Table 1. Cont.
403.2
413.2
413.2
423.2
423.2
433.2
433.2
443.2
methanol
n-hexane
methanol
n-hexane
methanol
n-hexane
methanol
n-hexane
2.7
13.5
2.7
90.3 ± 0.8
37.0 ± 3.0
232 ± 9
26
73.6 ± 7.0
29.4 ± 3.5
180 ± 13
67.3 ±3.5
405 ± 10
141 ± 4
14.5
26
13.5
2.7
87 ± 6.5
546 ± 21
222 ± 18
697 ± 8
14.5
26
13.5
54.0
13.5
14.5
13.0
14.5
706 ± 47
277 ± 18
532 ± 25
Note: a trioxane initial concentrations.
Figure 1. Arrhenius Equation Plots for the Thermolysis of Trioxanes I (...) and II (__) in
Solution.
Ln k (s-1)-4
y = -14.883x + 29.922
R2 = 0.9995
-5
-6
y = -14.016x + 25.795
R2 = 0.9997
-7
-8
y = -14.098x + 27.707
R2 = 0.9954
-9
y = -16.023x + 30.844
R2 = 0.9989
-10
-11
2.1
2.3
2.5
2.7
1000/T (K-1)
Symbols: ٱ, n-hexane, (13.5x10-5 M); ■, n-hexane, (14.5x10-5 M); ∆, methanol,
(13x10-5 M); ▲, methanol, (54x10-5 M).

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From the data a kinetic solvent effect in the thermolysis of I and II is evident, as the reaction rates, at
the same temperature, are faster in methanol than in n-hexane. Furthermore, the temperature effect on
the experimental rate constant values (kobs) in the solvents investigated can be represented by an
Arrhenius equation (Figure 1), where the error limits indicated are standard deviations from a least
mean-squares data treatment.
The linearity of these plots (R2 ≥ 0.9954) over a relatively large temperature range suggests that the
calculated activation parameters for I and II reactions (Table II) correspond to single processes.
Table II. Activation Parameters Valuesa for the Unimolecular
Thermolysis in Solution of Trioxanes I and II.
Reaction
Solvent
∆H#
∆S#
∆G#
Trioxane
kcal mol-1
cal mol-1 K-1
kcal mol-1
I
I
methanol
n-hexane
methanol
n-hexane
28.2 ± 0.7
31.1 ± 0.9
29.0 ± 0.7
31.7 ± 0.6
- 3.0 ± 1.3
0.4 ± 2.1
- 1.5 ± 1.8
0.7 ± 1.7
28.9 ± 0.7
30.9 ± 0.9
29.6 ± 0.7
31.4 ± 0.6
II
II
Note: a calculated at the middle of the experimental temperature range (see Table I).
These activation parameters can be assigned to the “in cage” unimolecular thermal cleavage of the
O-O bonds of I and II molecules as initial stages of their mechanisms of reaction (eq. 1).
. .
o
o
o
o
1
(
)
o
o
Moreover, if the unimolecular thermolyses of those molecules involve concerted bond breaking and
formation, the experimentally observed activation entropies (Table II) should be very negative. Hence,
it can be supposed that the activation parameters for the decomposition reactions of I and II in
n-hexane and methanol solutions correspond to their unimolecular homolysis, because alternative
reaction pathways can not be reasonably postulated. The ∆G# values for both trioxane reactions (Table
II) support similar interactions between substrate and the solvent molecules in each thermolysis.
Furthermore, the corresponding activation enthalpies of the reactions are almost compensated by the
entropies of activation, yielding practically the same values of the free energies of activation. Also the
analogous ∆H# values for both trioxane reactions (Table II) reflect that the unsaturated cyclopentene
rings of I and II molecules and the hydroxyl atomic group at the C-3 position of the latter, do not
influence the peroxydic bond strength of the trioxanes as already advanced [12].