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 temperature and concentration ranges of 393.2-443.2 K and 2.7-54 × 10-5 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.Facultad de Ciencias Exacta

Cafferata, Lázaro F. R.

Rimada, Rubén S.

Molecules

English

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

Lazaro F. R. Cafferata

Ruben S. Rimada

CiteSeerX

Solvent and Substituent Effects on the Thermolysis of Antimalarial Fluorophenyl Substituted 1,2,4Trioxanes

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Molecules 2003, 8, 655-662 molecules ISSN 1420-3049 http://www.mdpi.org  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   Molecules 2003, 8   656Introduction  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.  HFFOOO(I)                HOHOOOFF (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 M 105 ·kobs s-1 105·[II]a M 105·kobs s-1 393.2 n-hexane 13.5 5.1 ± 0.5 82 2.7 ± 0.2 393.2 methanol 2.7 38.2 ± 0.4 1.05 27.6 ± 3.0 403.2 n-hexane 13.5 14 ± 1.5 82 4.2 ± 0.4   Molecules 2003, 8   657Table 1. Cont.  403.2 methanol 2.7 90.3 ± 0.8 26 73.6 ± 7.0 413.2 n-hexane 13.5 37.0 ± 3.0 14.5 29.4 ± 3.5 413.2 methanol 2.7 232 ± 9 26 180 ± 13 423.2 n-hexane 13.5 87 ± 6.5 14.5 67.3 ±3.5 423.2 methanol 2.7 546 ± 21 26 405 ± 10 433.2 n-hexane 13.5 222 ± 18 14.5 141 ± 4 433.2 methanol 54.0 697 ± 8 13.0 706 ± 47 443.2 n-hexane 13.5 532 ± 25 14.5 277 ± 18 Note: a trioxane initial concentrations.  Figure 1. Arrhenius Equation Plots for the Thermolysis of Trioxanes I (...) and II (__) in Solution.   Symbols: ٱ, n-hexane, (13.5x10-5 M); ■, n-hexane, (14.5x10-5 M); ∆, methanol, (13x10-5 M); ▲, methanol, (54x10-5 M).   y = -14.883x + 29.922R2 = 0.9995y = -16.023x + 30.844R2 = 0.9989y = -14.016x + 25.795R2 = 0.9997y = -14.098x + 27.707R2 = 0.9954-11-10-9-8-7-6-5-42.1 2.3 2.5 2.71000/T (K-1)Ln k (s-1)Molecules 2003, 8   658   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.  Trioxane Reaction Solvent ∆H# kcal mol-1 ∆S# cal mol-1 K-1 ∆G# kcal mol-1         I               methanol  28.2 ± 0.7        - 3.0 ± 1.3           28.9 ± 0.7            I    n-hexane  31.1 ± 0.9          0.4 ± 2.1         30.9 ± 0.9           II     methanol  29.0 ± 0.7       -  1.5 ± 1.8        29.6 ± 0.7           II    n-hexane   31.7 ± 0.6     0.7 ± 1.7         31.4 ± 0.6    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).   oo o o o o . . ( 1 )      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].  Molecules 2003, 8   659Thus, the first step in the reactions of I and II is their unimolecular homolysis to give the corresponding substituted diradical (eq. 1), which undergoes subsequently further decompositions to finally yield the observed reaction products (Table III).           Table III. Products Molar Yieldsa Arising from the Thermolysis of I and  II in Different Solvents.   Trioxane    Solvent                       Reaction Products      I n-hexane      Cyclopentanone (5%); 1,3-di-(4-fluorophenyl)-3-cyclopenten-1-ol (18 %) ; 1,4-di-(4-fluorophenyl)-3-cyclopenten-1,2-diol (39 %).      I methanol Cyclopentanone (7%); 3-(4-fluorophenyl)-4-(4-fluorobenzoyl)-2-buthenal (6%); 3,5-di-(4-fluorophenyl)-5-methoxy-2-cyclopenten-1-ol (3%); 1,4-di-(4-fluorophenyl)-2-methoxy-3-cyclopenten-1-ol (3%); 1,4-di-(4-fluorophenyl)-3,4-dimethoxy-cyclopentene (2.5%); 1,1-methyl-methoxy-cyclopentane (8%); 4-fluorobenzoic acid (5%)     II n-hexane Cyclopentanone (6%); 4-(4-fluorobenzoyl)-3-(4-fluorophenyl)-2-hydroxy-3-butenal (13%); 1,3-di-(4-fluorophenyl)-2-cyclo-penten-1,4-diol (10 %).     II methanol Cyclopentanone (10%); 4-(4-fluorobenzoyl)-3-(4-fluorophenyl)-2-hydroxy-3-butenal (10%); 2,4-di-(4-fluorophenyl)-5-methyl-4-methoxy-2-cyclopeten-1-ol (3%); 2,4-di-(4-fluorophenyl)-4-methoxy-2-cyclopenten-1-ol (5%);  2,4-(4-fluorophenyl)-4,5-dimethoxy-2-cyclopenten-2-ol (3%); 1,1-methyl-methoxy-cyclopentane (10%); 1,3-di-(4-fluorophenyl)-5-methyl-2-cyclopenten-1,4-diol (2%). Note: a expressed in parenthesis as % of total GC-MS peak areas (MSD in TIC mode) of all products observed.  However, the decomposition of I differs from the reaction of II in some aspects. Not only is the kinetic solvent effect on the unimolecular homolysis quantitatively different, but the main products of the whole reactions are different too. In both solvents the trioxanes investigated furnished cyclopentanone in nearly molar yields (Table III), providing good evidence for the scission of the postulated initial diradical (eq. 1). Thus, the thermolyses of molecules I and II are similarly governed by the extrusion of stable fragments as cyclopentanone and other methoxy-substituted products, these evidently coming in the case of methanol solution, from the reaction of intermediate species with the molecules of the solvent (Table III).   Molecules 2003, 8   660Conclusions  Analysis of the kinetics and product distributions for the thermolysis of trioxanes I and II support the hypothesis of a solvent effect on the initial homolytic rupture of their O-O peroxydic bonds, which constitutes the rate determining step of both reactions. Substituent effects appear to have little influence on the decomposition kinetics. Furthermore, the present results parallel those obtained for the thermolysis of substituted 1,2,4,5-tetroxanes in solution [1], which also decompose by an unimolecular homolysis in a step-wise mechanism of reaction.  Experimental  General      The trioxanes cis-6-(4-fluorophenyl)-5,6-[2-(4-fluorophenyl)-propylidene]-3,3-tetramethylene-1,2,4-trioxacyclohexane (I) and cis-6-(4-fluorophenyl)-5,6-[2-(4-fluorophenyl)-3-hydroxy-propylidene]-3,3-tetramethylene-1,2,4-trioxacyclohexane (II) were obtained by methods mentioned elsewhere [13]. The purity of these substances was checked by appropriate RP-HPLC methods already reported [14]. The methanol and n-hexane employed were commercial analytical reagents purified by standard techniques [15] and further distillation from saturated solutions of ethylenediamine tetraacetic acid (EDTA). This treatment was carried out to remove traces of metallic ions, which might accelerate the thermolyses according to a previous report [2] for other cyclic peroxide reactions.   Kinetics and analytical methods  Pyrex glass tubes (6 cm length, 6 mm o.d., and ca. 1 mm wall thickness) half filled (ca. 0.4 mL) with the corresponding cyclic peroxide solutions, were thoroughly degassed under vacuum at 83 K and then sealed with a flame torch. To perform the kinetic runs the ampoules were immersed in a thermostated silicone oil bath (± 0.1 K) and withdrawn after selected times, stopping the reactions by cooling to 273 K. For monitoring the concentrations of the remaining 1,2,4-trioxanes in the solutions, as well as the organic reaction products, a RP-HPLC technique of analysis was employed [14] using a Pharmacia LKB instrument with a Spherisorb SuperPack RP-C18 column (ODS, 2.5 µm, 4.0 mm i.d., 100 mm length) at room temperature. In the present work mixtures of methanol 85%-water (v/v) were employed as mobile phases at 0.5 mL/min flow-rate (inlet pressure ca 9.0 mPa) for the analysis of the products of I reactions and methanol 75 %-water (v/v) for the analysis of II reactions, respectively. Samples (20 µL) or the standards dissolved in the same mixture of solvents were injected, using UV detection at 254 nm wavelength, for both monitoring the peak areas of I and II. The identification of the products of the thermolyses was performed by GC-MS analyses in a 5890 model, Series II Plus, Hewlett-Packard instrument, with helium as carrier gas, conveniently coupled to a 5972 A model, Hewlett-Packard MSD at 179 ºC, using a HP5 (cross-linked 5% phenyl methylsilicone) capillary silica Molecules 2003, 8   661fused column (30 m length, 0.25 mm i.d., 0.25 µm film thickness) programmed at 10°C/min rate from 50°C to 200 oC with the injector port temperature at 120°C (split mode).     The first-order rate constants values for the thermolysis of I and II were calculated by a least means square data treatment by plotting ln [trioxane concentration] vs. reaction time. The corresponding correlation factors obtained (r > 0.9950) were satisfactory considering the several experimental steps involved to get the final analytical data. The activation parameters values for the unimolecular reactions investigated were obtained applying the Eyring equation (k = kB T / h exp (-∆H# / RT) exp (∆S# / R), where (kB /h)  = 2.084 x 1010 degree-1 s-1 and R = 1.986 cal mol-1 K-1. Error limits were determined by a computational treatment of the data and using a reliable literature method [16].  References  1. Cafferata, L. F. R.; Furlong, J. J. "Thermolysis of Tetroxanes, in Advances in Oxygenated Processes, Baumstark, A. L.; Ed.; JAI Press Inc.: USA, 1995; Volume IV, 81-105.  2. Cafferata, L. F. R.; Nojima, M.; Yamakoshi, H. Kinetics and Mechanism of the Thermal Decomposition Reaction of Dyhydro-3,6-Diphenyl-5-Benzyl-1,2,4,5-Trioxazine. Int. J.  Chem. Kin. 1995, 28, 21-25.  3. Jefford, C. W.; Rossier, J. C.; Boukouvalas; J. C.  J. Chem. Soc., Chem. Commun., 1987, 713-716. 4. Cafferata, L. F. R.; Mirífico, M. V. Efectos de Solventes en la Cinética de la  Descomposición Unimolecular del Peróxido de Benzoílo, An. Asoc. Quím. Argentina, 1982, 70, 29-42. 5. Cafferata, L. F. R.; Quintáns, M. T. An. Asoc. Quím. Argentina, 1987, 75, 461-474. 6. Cafferata, L. F. R.; Eyler, G. N.; Svartman, E. L.; Cañizo, A.; Alvarez, E. Solvent effects in the Thermal Decomposition Reactions of Cyclic Ketone Diperoxides, J. Org. Chem., 1991, 56, 411-414.  7. Eyler, G. N.; Cañizo, A.; Alvarez, E.; Mateo, C.; Cafferata, L. F. R. Induced Decomposition Reaction in Solution of Acetone Derived Cyclic Peroxides, Afinidad, 2002, 59 (502), 684-687. 8. Leiva, L.; Castellanos, M. G.; Gómez Vara, M.; Cafferata  L. F. R. Thermolysis of  Benzaldehyde and Acetone Cyclic Diperoxide in Tetrahydrofurane Solution, Afinidad, 2002, 59 (502), 676-683. 9. Allegretti, P.; Rimada, R. S.; Furlong, J. J.; Cafferata, L. F. R. Mass Spectrometric Evidence for the Reaction Mechanism of Thermolysis of 1,2,4-trioxanes in Solution, Asian J. Spectrosc., 1998, 2, 165-172. 10. Cafferata, L. F. R.; Jefford, C. W.; Rimada, R. S. Kinetics and Mechanism of Thermolysis of Fluorine Substituted 1,2,4-trioxanes in Methanol Solution, Int. J. Chem. Kin.,  2000, 32, 523-528.  11. Cafferata, L. F. R.; Jefford, C. W.; Rimada, R. S. Kinetics and Mechanism of  Thermolysis of 1,2,4-trioxanes in n-hexane Solution, Afinidad, 2002, 59 (502), 670-675.  12. Cafferata, L. F. R.; Jefford, C. W.  Solvent and Substituent Effects on the Kinetics of     Thermolysis of cis-fused 1,2,4-Trioxanes, Molecules, 2001, 6, 699-709. 13. Jefford, C. W.; Kohmoto, S.; Joggi, D.; Rossier, J. C.; Timarí, G.; Ruday, M.; Barbuzzi, O.; Gérard, D.; Burger, U.; Kamalaprija, P.; Bernardinelli, G.; Canfield, C.; Fleck, B. I.; Robinson, R.; Molecules 2003, 8   662Peters, W. Synthesis, Structure and Antimalarial Activity of Some Enantiomerically Pure cis-fused Cyclopentene-1,2,4-trioxanes. Helv., Chim. Acta, 1995, 78, 647-655.  14. Cafferata, L. F. R.; Rimada, R. S.; Furlong, J. J.; Allegretti, P. RP-HPLC and GC-MS           Techniques for the Quantitative Analysis of Substituted 1,2,4-trioxanes and their           Thermolysis Products in Solution, J. High Resol. Chrom., 1999, 22, 67-70. 15. Bunnet. J. Investigation of Rates and Mechanism of Reaction, in Techniques of Chemistry, Weissberger, A., Ed.; Wiley: New York, 1974; Part I, Vol. VI, Chapter VIII. 16. Huyberechts, S.; Halleux, A.; Kruys, P. Une Aplication de Calcule Statistique a la Cinetique Chimique, Bull. Chim. Belg.. 1955, 64, 203-209.  Sample availability: Samples of compounds I and II are available from the authors.  © 2003 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.               

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

SEDICI - Repositorio de la UNLP

Molecules 2003, 8, 655-662 
molecules 
ISSN 1420-3049 
http://www.mdpi.org 
 
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 
 
 
Molecules 2003, 8 
 
 
656
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. 
 
H
F
F
O
O
O
(I)                
H
OH
O
O
O
F
F (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 
M 
105 ·kobs 
s-1 
105·[II]a 
M 
105·kobs 
s-1 
393.2 n-hexane 13.5 5.1 ± 0.5 82 2.7 ± 0.2 
393.2 methanol 2.7 38.2 ± 0.4 1.05 27.6 ± 3.0 
403.2 n-hexane 13.5 14 ± 1.5 82 4.2 ± 0.4 
 
 
Molecules 2003, 8 
 
 
657
Table 1. Cont. 
 
403.2 methanol 2.7 90.3 ± 0.8 26 73.6 ± 7.0 
413.2 n-hexane 13.5 37.0 ± 3.0 14.5 29.4 ± 3.5 
413.2 methanol 2.7 232 ± 9 26 180 ± 13 
423.2 n-hexane 13.5 87 ± 6.5 14.5 67.3 ±3.5 
423.2 methanol 2.7 546 ± 21 26 405 ± 10 
433.2 n-hexane 13.5 222 ± 18 14.5 141 ± 4 
433.2 methanol 54.0 697 ± 8 13.0 706 ± 47 
443.2 n-hexane 13.5 532 ± 25 14.5 277 ± 18 
Note: a trioxane initial concentrations. 
 
Figure 1. Arrhenius Equation Plots for the Thermolysis of Trioxanes I (...) and II (__) in 
Solution.  
 
Symbols: ٱ, n-hexane, (13.5x10-5 M); ■, n-hexane, (14.5x10-5 M); ∆, methanol, 
(13x10-5 M); ▲, methanol, (54x10-5 M).  
 
y = -14.883x + 29.922
R2 = 0.9995
y = -16.023x + 30.844
R2 = 0.9989
y = -14.016x + 25.795
R2 = 0.9997
y = -14.098x + 27.707
R2 = 0.9954
-11
-10
-9
-8
-7
-6
-5
-4
2.1 2.3 2.5 2.7
1000/T (K-1)
Ln k (s-1)
Molecules 2003, 8 
 
 
658
   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. 
 
Trioxane 
Reaction 
Solvent 
∆H# 
kcal mol-1 
∆S# 
cal mol-1 K-1 
∆G# 
kcal mol-1 
        I               methanol  28.2 ± 0.7        - 3.0 ± 1.3           28.9 ± 0.7    
        I    n-hexane  31.1 ± 0.9          0.4 ± 2.1         30.9 ± 0.9    
       II     methanol  29.0 ± 0.7       -  1.5 ± 1.8        29.6 ± 0.7    
       II    n-hexane   31.7 ± 0.6     0.7 ± 1.7         31.4 ± 0.6    
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 
o 
o . . ( 1 )
 
 
    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].  
Molecules 2003, 8 
 
 
659
Thus, the first step in the reactions of I and II is their unimolecular homolysis to give the 
corresponding substituted diradical (eq. 1), which undergoes subsequently further decompositions to 
finally yield the observed reaction products (Table III). 
          
Table III. Products Molar Yieldsa Arising from the Thermolysis of I and  
II in Different Solvents. 
 
 Trioxane    Solvent                       Reaction Products 
     I n-hexane      Cyclopentanone (5%); 1,3-di-(4-fluorophenyl)-3-cyclopenten-1-
ol (18 %) ; 1,4-di-(4-fluorophenyl)-3-cyclopenten-1,2-diol (39 
%). 
     I methanol Cyclopentanone (7%); 3-(4-fluorophenyl)-4-(4-fluorobenzoyl)-2-
buthenal (6%); 3,5-di-(4-fluorophenyl)-5-methoxy-2-
cyclopenten-1-ol (3%); 1,4-di-(4-fluorophenyl)-2-methoxy-3-
cyclopenten-1-ol (3%); 1,4-di-(4-fluorophenyl)-3,4-dimethoxy-
cyclopentene (2.5%); 1,1-methyl-methoxy-cyclopentane (8%); 4-
fluorobenzoic acid (5%) 
    II n-hexane Cyclopentanone (6%); 4-(4-fluorobenzoyl)-3-(4-fluorophenyl)-2-
hydroxy-3-butenal (13%); 1,3-di-(4-fluorophenyl)-2-cyclo-
penten-1,4-diol (10 %). 
    II methanol Cyclopentanone (10%); 4-(4-fluorobenzoyl)-3-(4-fluorophenyl)-
2-hydroxy-3-butenal (10%); 2,4-di-(4-fluorophenyl)-5-methyl-4-
methoxy-2-cyclopeten-1-ol (3%); 2,4-di-(4-fluorophenyl)-4-
methoxy-2-cyclopenten-1-ol (5%);  2,4-(4-fluorophenyl)-4,5-
dimethoxy-2-cyclopenten-2-ol (3%); 1,1-methyl-methoxy-
cyclopentane (10%); 1,3-di-(4-fluorophenyl)-5-methyl-2-
cyclopenten-1,4-diol (2%). 
Note: a expressed in parenthesis as % of total GC-MS peak areas (MSD in TIC mode) 
of all products observed. 
 
However, the decomposition of I differs from the reaction of II in some aspects. Not only is the 
kinetic solvent effect on the unimolecular homolysis quantitatively different, but the main products of 
the whole reactions are different too. In both solvents the trioxanes investigated furnished 
cyclopentanone in nearly molar yields (Table III), providing good evidence for the scission of the 
postulated initial diradical (eq. 1). Thus, the thermolyses of molecules I and II are similarly governed 
by the extrusion of stable fragments as cyclopentanone and other methoxy-substituted products, these 
evidently coming in the case of methanol solution, from the reaction of intermediate species with the 
molecules of the solvent (Table III).  
 
Molecules 2003, 8 
 
 
660
Conclusions 
 
Analysis of the kinetics and product distributions for the thermolysis of trioxanes I and II support 
the hypothesis of a solvent effect on the initial homolytic rupture of their O-O peroxydic bonds, which 
constitutes the rate determining step of both reactions. Substituent effects appear to have little 
influence on the decomposition kinetics. Furthermore, the present results parallel those obtained for the 
thermolysis of substituted 1,2,4,5-tetroxanes in solution [1], which also decompose by an unimolecular 
homolysis in a step-wise mechanism of reaction. 
 
Experimental 
 
General 
     
The trioxanes cis-6-(4-fluorophenyl)-5,6-[2-(4-fluorophenyl)-propylidene]-3,3-tetramethylene-
1,2,4-trioxacyclohexane (I) and cis-6-(4-fluorophenyl)-5,6-[2-(4-fluorophenyl)-3-hydroxy-
propylidene]-3,3-tetramethylene-1,2,4-trioxacyclohexane (II) were obtained by methods mentioned 
elsewhere [13]. The purity of these substances was checked by appropriate RP-HPLC methods already 
reported [14]. The methanol and n-hexane employed were commercial analytical reagents purified by 
standard techniques [15] and further distillation from saturated solutions of ethylenediamine tetraacetic 
acid (EDTA). This treatment was carried out to remove traces of metallic ions, which might accelerate 
the thermolyses according to a previous report [2] for other cyclic peroxide reactions.  
 
Kinetics and analytical methods 
 
Pyrex glass tubes (6 cm length, 6 mm o.d., and ca. 1 mm wall thickness) half filled (ca. 0.4 mL) 
with the corresponding cyclic peroxide solutions, were thoroughly degassed under vacuum at 83 K and 
then sealed with a flame torch. To perform the kinetic runs the ampoules were immersed in a 
thermostated silicone oil bath (± 0.1 K) and withdrawn after selected times, stopping the reactions by 
cooling to 273 K. For monitoring the concentrations of the remaining 1,2,4-trioxanes in the solutions, 
as well as the organic reaction products, a RP-HPLC technique of analysis was employed [14] using a 
Pharmacia LKB instrument with a Spherisorb SuperPack RP-C18 column (ODS, 2.5 µm, 4.0 mm i.d., 
100 mm length) at room temperature. In the present work mixtures of methanol 85%-water (v/v) were 
employed as mobile phases at 0.5 mL/min flow-rate (inlet pressure ca 9.0 mPa) for the analysis of the 
products of I reactions and methanol 75 %-water (v/v) for the analysis of II reactions, respectively. 
Samples (20 µL) or the standards dissolved in the same mixture of solvents were injected, using 
UV detection at 254 nm wavelength, for both monitoring the peak areas of I and II. The identification 
of the products of the thermolyses was performed by GC-MS analyses in a 5890 model, Series II Plus, 
Hewlett-Packard instrument, with helium as carrier gas, conveniently coupled to a 5972 A model, 
Hewlett-Packard MSD at 179 ºC, using a HP5 (cross-linked 5% phenyl methylsilicone) capillary silica 
Molecules 2003, 8 
 
 
661
fused column (30 m length, 0.25 mm i.d., 0.25 µm film thickness) programmed at 10°C/min rate from 
50°C to 200 oC with the injector port temperature at 120°C (split mode). 
    The first-order rate constants values for the thermolysis of I and II were calculated by a least means 
square data treatment by plotting ln [trioxane concentration] vs. reaction time. The corresponding 
correlation factors obtained (r > 0.9950) were satisfactory considering the several experimental steps 
involved to get the final analytical data. The activation parameters values for the unimolecular 
reactions investigated were obtained applying the Eyring equation (k = kB T / h exp (-∆H# / RT) exp 
(∆S# / R), where (kB /h)  = 2.084 x 1010 degree-1 s-1 and R = 1.986 cal mol-1 K-1. Error limits were 
determined by a computational treatment of the data and using a reliable literature method [16]. 
 
References 
 
1. Cafferata, L. F. R.; Furlong, J. J. "Thermolysis of Tetroxanes, in Advances in Oxygenated 
Processes, Baumstark, A. L.; Ed.; JAI Press Inc.: USA, 1995; Volume IV, 81-105.  
2. Cafferata, L. F. R.; Nojima, M.; Yamakoshi, H. Kinetics and Mechanism of the Thermal 
Decomposition Reaction of Dyhydro-3,6-Diphenyl-5-Benzyl-1,2,4,5-Trioxazine. Int. J.  Chem. 
Kin. 1995, 28, 21-25.  
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Sample availability: Samples of compounds I and II are available from the authors. 
 
© 2003 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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

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