TY - JOUR
T1 - Reaction pathways and free energy barriers for alkaline hydrolysis of insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds
T2 - Electrostatic and steric effects
AU - Xiong, Ying
AU - Zhan, Chang Guo
PY - 2004/11/26
Y1 - 2004/11/26
N2 - Reaction pathways and free energy barriers for alkaline hydrolysis of the highly neurotoxic insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds were studied by performing first-principles electronic structure calculations on representative methyl phosphonofluoridates, (RO)CH3P(O)F, in which R = CH 2CH2N+(CH3)3, CH 3, CH2CH2C(CH3)3, CH 2CH2CH(CH3)2, CH(CH 3)CH2N+(CH3)3, and CH(CH3)CH2N(CH3)2. The dominant reaction pathway was found to be associated with a transition state in which the attacking nucleophile OH- and the leaving group F- are positioned on opposite sides of the plane formed by the three remaining atoms attached to the phosphorus in order to minimize the electrostatic repulsion between these two groups. The free energy barriers calculated for the rate-determining step of the dominant pathway are 12.5 kcal/mol when R = CH 2CH2N+(CH3)3, 15.5 kcal/mol when R = CH3, 17.9 kcal/mol when R = CH2CH 2C(CH3)3, 16.5 kcal/mol when R = CH 2CH2CH(CH3)2, 13.4 kcal/mol when R = CH(CH3)CH2N+(CH3)3, and 18.7 kcal/mol when R = CH(CH3)CH2N(CH3) 2. The calculated free energy barriers are in good agreement with available experimentally derived activation free energies, i.e. 14.7 kcal/mol when R = CH3, 13.4 kcal/mol when R = CH2CH 2N+-(CH3)3, and 13.9 kcal/mol when R = CH(CH3)CH2N+(CH3)3. A detailed analysis of the calculated energetic results and available experimental data suggests that the net charge of the molecule (M) being hydrolyzed is a prominent factor affecting the free energy barrier (ΔG) for the alkaline hydrolysis of phosphodiesters, phosphonofluoridates, and related organophosphorus compounds. The electrostatic interactions between the attacking nucleophile OH- and the molecule M being hydrolyzed favor such an order of the free energy barrier: ΔG(M++OH-) < ΔG(M0+OH-) < ΔG(M-+OH -), where M+, M0, and M- represent the cationic, neutral, and anionic molecules, respectively. The change of the substituent R in (RO)CH3P(O)F from CH3 to CH 2CH2N+(CH3)3 is associated with both the electrostatic and steric effects on the free energy barrier, but the electrostatic effect dominates the substituent shift of the free energy barrier. This helps to better understand why the alkaline hydrolysis of (RO)CH3P(O)F with R = CH2CH2N +(CH3)3 and CH(CH3)CH 2N+(CH3)3 is significantly faster than that with R = CH3. The effect of electrostatic interaction also helps to understand why the rate constants for the alkaline hydrolysis of phosphodiesters, such as intramolecular second messenger adenosine 3′,5′-phosphate (cAMP), are generally smaller than those for the alkaline hydrolysis of the phosphonofluoridates and related phosphotriesters.
AB - Reaction pathways and free energy barriers for alkaline hydrolysis of the highly neurotoxic insecticide 2-trimethylammonioethyl methylphosphonofluoridate and related organophosphorus compounds were studied by performing first-principles electronic structure calculations on representative methyl phosphonofluoridates, (RO)CH3P(O)F, in which R = CH 2CH2N+(CH3)3, CH 3, CH2CH2C(CH3)3, CH 2CH2CH(CH3)2, CH(CH 3)CH2N+(CH3)3, and CH(CH3)CH2N(CH3)2. The dominant reaction pathway was found to be associated with a transition state in which the attacking nucleophile OH- and the leaving group F- are positioned on opposite sides of the plane formed by the three remaining atoms attached to the phosphorus in order to minimize the electrostatic repulsion between these two groups. The free energy barriers calculated for the rate-determining step of the dominant pathway are 12.5 kcal/mol when R = CH 2CH2N+(CH3)3, 15.5 kcal/mol when R = CH3, 17.9 kcal/mol when R = CH2CH 2C(CH3)3, 16.5 kcal/mol when R = CH 2CH2CH(CH3)2, 13.4 kcal/mol when R = CH(CH3)CH2N+(CH3)3, and 18.7 kcal/mol when R = CH(CH3)CH2N(CH3) 2. The calculated free energy barriers are in good agreement with available experimentally derived activation free energies, i.e. 14.7 kcal/mol when R = CH3, 13.4 kcal/mol when R = CH2CH 2N+-(CH3)3, and 13.9 kcal/mol when R = CH(CH3)CH2N+(CH3)3. A detailed analysis of the calculated energetic results and available experimental data suggests that the net charge of the molecule (M) being hydrolyzed is a prominent factor affecting the free energy barrier (ΔG) for the alkaline hydrolysis of phosphodiesters, phosphonofluoridates, and related organophosphorus compounds. The electrostatic interactions between the attacking nucleophile OH- and the molecule M being hydrolyzed favor such an order of the free energy barrier: ΔG(M++OH-) < ΔG(M0+OH-) < ΔG(M-+OH -), where M+, M0, and M- represent the cationic, neutral, and anionic molecules, respectively. The change of the substituent R in (RO)CH3P(O)F from CH3 to CH 2CH2N+(CH3)3 is associated with both the electrostatic and steric effects on the free energy barrier, but the electrostatic effect dominates the substituent shift of the free energy barrier. This helps to better understand why the alkaline hydrolysis of (RO)CH3P(O)F with R = CH2CH2N +(CH3)3 and CH(CH3)CH 2N+(CH3)3 is significantly faster than that with R = CH3. The effect of electrostatic interaction also helps to understand why the rate constants for the alkaline hydrolysis of phosphodiesters, such as intramolecular second messenger adenosine 3′,5′-phosphate (cAMP), are generally smaller than those for the alkaline hydrolysis of the phosphonofluoridates and related phosphotriesters.
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U2 - 10.1021/jo0487597
DO - 10.1021/jo0487597
M3 - Article
C2 - 15549820
AN - SCOPUS:9344264066
SN - 0022-3263
VL - 69
SP - 8451
EP - 8458
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
IS - 24
ER -