Hetero Diels-Alder Adduct Formation between Nitrosobenzene and Tetra-methyl Purpurogallin and its retro-Diels-Alder Reaction

The renewed interest in both natural and semisynthetic endoperoxides and NO-containing products, both of which present interesting medicinal applications 1-5, led us to reconsider the preparation of these structures through DielsAlder reactions. Heteroatomic functional arrangements can result in dienophiles which react to produce heterocyclic Diels-Alder adducts 6,7. Some di-heteroatomic systems, such as O=O, O=N and N=N, also show this behavior, with the formation of di-heteroatomic cyclic structures 6,8-11. Nitroso compounds, in particular, are known to give oxazine type adducts 12-15. Adequately substituted tropolones and benzotropolones behave as dienes in Diels-Alder reactions, both with homoand heteroaromatic (Figure 1. I from TMPG and II from eucarvone) dienophiles 8,9,10,14. Peroxo TMPG ( I ) is thermally unstable, and breakage of the peroxide bond results in a rearranged product 8,9. In the case of NO bond the thermal behavior is different, giving way to a facile retro Diels-Alder reaction with quantitative recovery of both diene and dienophile. Adducts from thebaine acting as diene and nitrosoarenes as dienophiles show different degrees of dissociation, depending on the electronic characteristics of the substituents placed parato the nitroso group in the nitrosoarenes 15. We here describe the preparation of the tetramethyl purpurogallin and nitrosobenzene Diels-Alder adduct, together with the determination of the rates of the retroDiels-Alder reaction.

Peroxo TMPG (I) is thermally unstable, and breakage of the peroxide bond results in a rearranged product 8,9 .In the case of NO bond the thermal behavior is different, giving way to a facile retro Diels-Alder reaction with quantitative recovery of both diene and dienophile.Adducts from thebaine acting as diene and nitrosoarenes as dienophiles show different degrees of dissociation, depending on the electronic characteristics of the substituents placed para-to the nitroso group in the nitrosoarenes 15 .
We here describe the preparation of the tetramethyl purpurogallin and nitrosobenzene Diels-Alder adduct, together with the determination of the rates of the retro-Diels-Alder reaction.

Results and Discussion
The adduct was obtained both in polar (methanol, diethyl ether) and non-polar solvents (dichloromethane, toluene, hexane).In polar solvents the reaction was not complete giving rise to mixtures of unreacted starting products and the adduct.Using hexane the adduct could be isolated in good yields and purified.
The structure of the TMPG-NOB Diels-Alder adduct (Figure 2) was characterized by 1 H NMR, 13 C NMR and confirmed by X-Ray diffractometry 16 .Of the two possible orientations of the N-O bridge, only III was observed.
The thermal decomposition of the adduct proceeds through a retro-Diels-Alder mechanism as it is shown by *e-mail : pmoyna@bilbo.edu.uy 1 H NMR experiments, in which the coexistence of the three compounds involved in the reaction could be detected at the equilibrium point.When using an initial adduct concentration of 10 mg/mL the dissociation of the adduct was 60 % at 30°C, 78 % at 40°C and 86 % at 50°C.To establish the kinetic parameters for the retro-Diels-Alder we studied the intensity variations in the 1 H NMR signals for specific protons (H-9 and H-9'), both of the adduct and starting materials.The experiments were carried out in CDCl 3 solution at 30° and 50° with an initial adduct concentration (Ci) of 10 mg/mL, and at 40 °C with (Ci) = 5, 10, and 15 mL.Kinetic law at 40° C and direct rate constant (k 1 ) were determined using the differential method, studying the system at the start of the reaction 17 .
Activation energy (Ea) was calculated using Arrhenius equation:

Conclusions
The Diels-Alder reaction of TMPG and NOB in hexane resulted in the formation of the TMPG-NOB adduct as a crystalline solid.The structure could be established by spectroscopic methods and X-ray diffraction.
The kinetic and thermodynamic characteristics of the decomposition reaction at three temperatures were studied.Rate law, rate constant of the direct and inverse reaction at 40°C and the activation energy of the reaction were determined.The concentration of each species in equilibrium was established by observation of the 1 H NMR signals for specific protons.
The equilibrium in the retro-Diels-Alder reaction of TMPG-NOB was characterized by the determination of the thermodynamic constants ∆G°, ∆H° and ∆S°.The ∆G° value of approximately 2 kcal/mol is low, which is borne out by the facile formation and decomposition of the adduct where the direction of the reaction controlled simply by displacing the product from solution or eliminating one of the reactants from the mixture.The ∆H° value for the reaction (approximately 14 kcal/mol) indicates that while the adduct is stable once formed, it can be decomposed with a small energy outlay, for both of the liberated moities recover their condition of free aromatic systems.While there is a strict control of the orientation of the reactants leading to the adduct, ∆S° is not influenced by temperature.Table 1.

∆Gº = -RTln Keq
(3) These results indicate that there is the possibility of modulating the rates of the Diels-Alder and retro-Diels-Alder reactions by controlling the aromaticity of starting materials.A series of compounds and derivatives capable of liberating NO containing moieties has been planned to further study their stability, decomposition patterns and pharmacological properties.

Experimental
General NMR Spectra were measured in a Bruker Avance 400 DPX.
Kinetic studies were measured by 1 H NMR at 400 MHz using CDCl 3 (Aldrich 99.8% pure) as solvent.
IR spectra were measured in a FT-IR DR-8031 Shimadzu spectrophotometer in KBr pellets.
UV spectra were measured in a Unicam SP 800 ultraviolet spectrophotometer.
MS were measured in a Shimadzu GC-MS QP 1100 EX.Sample ionization was carried out by electron impact (20 and 70 eV).
Solvents were distilled in glass prior to use.

Tetra-O-methyl purpurogallin
Tri-O-methyl purpurogallin (5 g, 0.02 mol) and aqueous potassium hydroxide (32.5 g, 0.58 mol in 50 mL) were shaken until an homogeneous mixture was obtained.Dimethylsulfate (10 mL) was added in one portion, and the mixture warmed over a free flame until a reaction ensued.The flame was then removed, and after the first violent reaction had subsided, the mixture was boiled for a further 30 minutes.The reaction mixture was cooled to room temperature, the solid collected and washed with water.The solid was then dried and extracted with a large volume or diethyl ether.The ether extract was dried (MgSO 4 ), and the solvent removed to yield tetra-O-methyl purpurogallin (45 g, 86 %, m.p. 87-88 ºC).Recrystallization from methanol yields the pure compound, m.p. 92-93 ºC 20 .IR (KBr): ν max /cm -1 = 2943.7,1647.4,1620.