A DFT study of the ring opening mechanism of tetraethyl-2-aryl- 1,2-epoxygembisphosphonate

Transcription

1 A DFT study of the ring opening mechanism of tetraethyl-2-aryl- 1,2-epoxygembisphosphonate Ephraim F. Marondedze [a], Xavier Y. Mbianda [a], Thishana Singh [b] and enny. Govender *[a] [a] Department of Applied hemistry, University of Johannesburg, Box 17011, Doornfontein, 2028, Johannesburg, South Africa. [b] Department of hemistry, Durban University of Technology, Box 1334, Durban, 4000, South Africa.

2 Introduction istory of diphosphonates dates as far back to the mid-1800s. Today they are commonly referred to as bisphosphonates. R2 R In the medical field bisphosphonates: class of drugs that are used for: the prevention and treatment of rheumatoid arthritis, osteoporosis and aget s disease, also used to reduce pain in breast and lung cancer patients.

3 Introduction R2 R 1 on-nitrogen containing itrogen containing - - Bisphosphonate R 1 R Etidronic acid -l -l lodronic acid Tiludronic acid - S l amidronic acid Risedronic acid Zoledronic acid - lassified as either nitrogen containing or non-nitrogen containing bisphosphonates. itrogen containing bisphosphonates are known to exhibit high potency when compared to non-nitrogen containing bisphosphonates. Figure 1. Examples of non-nitrogen containing and nitrogen containing bisphosphonates the pharmaceutical industry.

4 Et Et R 1 Et Et R =Aryl group Introduction - Butanone, nbu 4.S4 p= , 22 o R 1 Et Et Et Et Figure 2. Synthesis of 2-aryl 1,2-epoxyethyl gembisphosphonates. Mbianda and co-workers (UJ) reported the synthesis of 2-aryl 1,2-epoxyethyl gembisphosphonates via dioxirane oxidation of vinylgembisphosphonates (Figure 2) First report of the epoxidation of substituted vinylgembisphosphonates featuring this class of epoxides. Reported new structures are of significant biological interest, since they may serve as important precursors for the synthesis of biologically active amino bisphosphonic acids.

5 Introduction Theoretically examine the opening of the oxirane ring of tetraethyl-2-aryl-1,2-epoxygembisphosphonate using ammonia as the simplest nucleophile. 1 B 2 A Reactant Epoxide ring opening is usually associated with regioselectivity making both the α- and β-carbon vulnerable to attack depending: on the reaction conditions, and the substituent on the oxirane ring. Thus the two mechanisms proposed (Figure 3) is based on nucleophilic attack at either 2 or 1. This study included the effect of varying the substituent on 2 as well as the effect of various solvents.

6 Introduction TS 1 roduct 1 Reactant roduct 2 TS A B A B mechanism 1 mechanism 2 Figure 3. A: roposed mechanism 1: ring opening at 2; B: roposed mechanism 2: ring opening at 1.

7 omputational Details B86 functional, basis set combination:aug-cc-pvtz for phosphorus and G (d,p) for,,, Frequency calculations: to identify the stationary point as a minimum (zero imaginary frequency) and transition state (one imaginary frequency) and to provide all the thermochemical data Intrinsic reaction coordinate (IR) calculations: to confirm that the TS connects the correct reactant and product on the ES. Effects of solvation: four polar solvents: 2, Me, TF and toluene (TL); and two dipolar solvents: dimethyl sulfoxide (DMS) and dichloromethane (DM). All the calculations were carried out with Gaussian 09 version D01.

8 Results and Discussion Ammonia attaching at either 2 or 1 resulted in a 4- membered cyclic transition state and then proceeded to the product. TS 1 roduct 1 Reactant roduct 2 TS A B A B mechanism 1 mechanism 2

9 Results and Discussion Frequency calculation: single negative value of cm -1, showed the breaking of the 2-51 epoxide bond which has lengthened to 2.20 Å; atom 53, from ammonia, moving towards 2 and, proton 52, from ammonia, attaching to 3 forming roduct 1 Figure 4. 4-membered TS 1 for mechanism 1

10 Figure 5: IR for TS 1

11 Results and Discussion Table 1: Summary of the relative a thermochemical data for mechanism 1 and 2 in the gas phase ΔE (kcal mol -1 ) Δ (kcal mol -1 ) ΔG (kcal mol -1 ) ΔS (cal K mol -1 ) E a (kcal mol -1 ) ln A Reactant TS TS roduct roduct a Energies are relative to Reactant (the energy of the starting materials). Table 2: Summary of the relative energies a (ΔE/kcal mol -1 ) for mechanism 1 and 2 in various solvents 2 Me TF DMS TL DM Reactant TS TS roduct roduct a Energies are relative to Reactant (the energy of the starting materials). At room temperature all molecules have an average thermal energy of 0.6 kcal.mol -1. So if the energy barrier, that the starting materials need to overcome before they can react to form the product, is as high as 25 kcal.mol -1, then heat must be added to the reaction.

12 Results and Discussion hange the substituent on 2 to lower the energy 1 2 R 1 2 R R Reactant TS 3-7 roduct 3-7 R = TS 3 F F 3 3 TS 4 TS 5 TS 6 TS 7 Figure 6. Electron-withdrawing and -donating substituents

13 Results and Discussion R = F F R TS 3 TS 4 TS 5 TS 6 TS 7 Reactant Table 3: Summary of the relative a thermochemical data for electron-withdrawing and -donating groups in the gas phase ΔE(kcal mol -1 ) Δ(kcal mol -1 ) ΔG(kcal mol -1 ) ΔS(cal K mol -1 ) E a (kcal mol -1 ) ln A Reactant TS TS TS TS TS roduct roduct roduct roduct roduct a Energies are relative to Reactant (the energy of the starting materials).

14 Results and Discussion R = F F R TS 3 TS 4 TS 5 TS 6 TS 7 Reactant Table 4: Summary of the relative energies a (ΔE/kcal mol -1 ) for electron-withdrawing and -donating groups in various solvents 2 Me TF DMS TL DM Reactant TS TS TS TS TS roduct roduct roduct roduct roduct a Energies are relative to Reactant (the energy of the starting materials).

15 onclusion Gas phase Relative Energy ( E)\ kcal. mol A Reactant TS 7 (24.23) (18.90) Reaction oordinate 3 (-18.48) (-21.78) Solvent TF roduct 7 Figure 7. Relative energy reaction profile for TS 7 in gas and solvent 3 Ring opening is favoured at the less hindered 2 of the oxirane ring. Variation of the substituent on 2 revealed electron-donating methoxybenzene to be the best substituent in this study. Further work: attempt using methanol as the nucleophile and, Vary the substituent on 2 using different electron-donating groups.

16 Acknowledgments Ephraim F. Marondedze