C. Tony Liu

Biomimetic Cleavage of RNA Models Promoted by a Dinuclear Zn(II) Complex in Ethanol. Greater than 30 kcal/mol Stabilization of the Transition State for Cleavage of a Phosphate Diester

The cleavage of a series of seven substituted aryl 2-hydroxypropyl phosphates (1a-g) promoted by a dinuclear Zn(II) complex (3:Zn(II)2:(-OCH2CH3)) was investigated in ethanol at pH 9.0 +/- 0.2 and 25 degrees C. The kinetics for appearance of the product phenols follow very strong saturation behavior for all substrates where the dissociation constant of the bound complex has an upper limit of Km = 3 x 10(-7) M and the k(cat)(max corr.) values (corrected for triflate inhibition) range from 168 to 3 s(-1). A partial s(s)pH/log k(cat)(max corr). profile for the 3:Zn(II)2:(-OCH2CH3)-catalyzed reaction of le (3-methoxyphenyl 2-hydroxypropyl phosphate) is bell-shaped, plateauing from 7.9-10, and is fit to a two kinetically important ionizations having s(s)pKa values of 7.22 and 10.9. The Brønsted plot of log (k(cat)(max corr.)) vs. the s(s)pKa values for the phenols shows a break at about 14.3 with two beta(lg), values of -1.12 and 0.0. This is analyzed in terms of a change in rate limiting step from cleavage of the phosphate to a conformational change where the binding of the phosphate changes from one P-O- ----Zn(II) interaction to a Zn(II)----O-P-O---Zn(II) double activation. An energetics calculation comparing the ethoxide promoted cleavage of 1a-g with the 3:Zn(ll)2:(-OEt) promoted reaction indicates that the complex, 3:Zn(II)2, stabilizes the ethoxide plus substrate transition state for the cleavage of 1a-g by between 33 and 36 kcal/mol. The origins of the large stabilization are discussed in terms of the effect of the medium on the various rate and equilibrium constants involved.

Leaving Group Assistance in the La3+-Catalyzed Cleavage of Dimethyl (o-Methoxycarbonyl)aryl Phosphate Triesters in Methanol

The catalytic methanolysis of a series of dimethyl aryl phosphate triesters where the aryl groups contain an o-methoxycarbonyl (o-CO2Me) substituent (4a-i) was studied at 25 degrees C in methanol containing La3+ at various concentrations and (s)(s)pH. Determination of the second-order rate constant for La3+(2)-catalyzed cleavage of substrate 4a (dimethyl (o-methoxycarbonyl)phenyl phosphate) as a function of (s)(s)pH was assessed in terms of a speciation diagram that showed that the process was catalyzed by La3+(2)(-OCH3)x dimers, where x = 1-5, that exhibit only a 5-fold difference in activity between all the species. The second-order catalytic rate constants (k2(La)) for the catalyzed methanolysis of 4a-i at (s)(s)pH 8.7 fit a Brønsted relationship of log k2(La) = (-0.82 +/- 0.11)(s)(s)pKa(lg) + (11.61 +/- 1.48), where the gradient is shallower than that determined for a series of dimethyl aryl phosphates that do not contain the o-CO2Me substituent, log k2(La) = (-1.25 +/- 0.06)(s)(s)pKa(lg) + (16.23 +/- 0.75). Two main observations are that (1) the o-CO2Me group preferentially accelerates the cleavage of the phosphate triesters with poor leaving groups relative to those with good leaving groups and (2) it provides an increase in cleavage rate relative to those of comparable substrates that do not have that functional group, e.g., k2(La)(dimethyl o-(methoxycarbonyl)phenyl phosphate)/k2(La)(dimethyl phenyl phosphate) = 60. Activation parameters for the La3+(2)-catalyzed methanolysis of 4a and dimethyl 4-nitrophenyl phosphate show respective DeltaH(double dagger) (DeltaS(double dagger)) values of 3.3 kcal/mol (-47 cal/mol x K) and 0.7 kcal/mol (-46.5 cal/mol x K). The data are analyzed in terms of a concerted reaction where the catalytic complex (La3+(2)(-OCH3)(x-1)) binds to the three components of a rather loose transition state composed of a nucleophile CH3O-, a nucleofuge -OAr, and a central (RO)2P(2+)-O(-) in a way that provides leaving group assistance to the departing aryloxy group.

Comparison of Cu(II)-Promoted Leaving Group Stabilization of the Cleavage of a Homologous Set of Phosphate Mono-, Di-, and Triesters in Water, Methanol, and Ethanol

The cleavage of a set of phosphate mono-, di-, and triesters having a Cu(II)-complexed 2-phenanthrolyl group at the ortho-position of a departing phenoxide was studied in water and ethanol. Experimentally observed pH/rate profiles, solvent deuterium kinetic isotope effects, and activation parameters are compared with those obtained in methanol. The pH/rate profile in each solvent exhibits an extended plateau due to solvent attack on forms designated as [Cu(II):1b/c](0) for the monoester, [Cu(II):2b](+), for the diester, and [Cu(II):3a](2+) for the triester. The solvent dkie values (k(H)/k(D)) for the three complexes are 0.91, 0.95, and 0.83 for decomposition of [Cu(II):1b/c](0) in water (W), methanol (M), and ethanol (E), 1.22, 1.09, and 1.29 for [Cu(II):2b](+) in W, M, and E, and 1.94, 2.2, and 1.96 for [Cu(II):3a](2+) in W, M, and E. Near unit, or slightly inverse values for the monoester are taken as evidence for little involvement of solvent in a highly dissociative TS for P-OAr cleavage, with slightly higher solvent dkie values for the diester signifying the onset of some solvent participation in assisting the nucleophilic displacement. The larger primary dkie for the triester gives evidence for a solvent-assisted delivery of ROH in the cleavage through a more associative mechanism. Activation parameters for each substrate in the solvents are compared, indicating that the transition from methanol to ethanol for each substrate involves a near cancellation of the ΔΔH(‡) and -TΔΔS(‡) values (25 °C) so that the respective rates in both solvents are very similar. The transition from alcohol to water produces variable effects, with ΔΔH(‡) and -TΔΔS(‡) values canceling for cleavage of the triester and being additive for the mono and diester, explaining their 100-500 rate reduction in passing from methanol to water. The rate enhancing effects of the Cu(II)-promoted leaving group assistance in all three solvents are substantial and estimated at 10(12)-10(15) for the monoester, 10(12)-10(14) for the diester, and 10(5) for the triester relative to their background reactions.

Mechanistic and computational study of a palladacycle-catalyzed decomposition of a series of neutral phosphorothioate triesters in methanol.

The methanolytic cleavage of a series of O,O-dimethyl O-aryl phosphorothioates (1a−g) catalyzed by a C,N-palladacycle, (2-[N,N-dimethylamino(methyl)phenyl]-C1,N)(pyridine) palladium(II) triflate (3), at 25 °C and sspH 11.7 in methanol is reported, along with data for the methanolytic cleavage of 1a−g. The methoxide reaction gives a linear log k2−OMe vs sspKa (phenol leaving group) Brønsted plot having a gradient of βlg = −0.47 ± 0.03, suggesting about 34% cleavage of the P−OAr bond in the transition state. On the other hand, the 3-catalyzed cleavage of 1 gives a Brønsted plot with a downward break at sspKa (phenol) 13, signifying a change in the rate-limiting step in the catalyzed reaction, with the two wings having βlg values of 0.0 ± 0.03 and −1.93 ± 0.06. The rate-limiting step for good substrates with low leaving group sspKa values is proposed to be substrate/pyridine exchange on the palladacycle, while for substrates with poor leaving groups, the rate-limiting step is a chemical one with extensive cleavage of the P−OAr bond. DFT calculations support this process and also identify two intermediates, namely, one where substrate/pyridine interchange has occurred to give the palladacycle coordinated to substrate through the S═P linkage and to methoxide (6) and another where intramolecular methoxide attack has occurred on the P═S unit to give a five-coordinate phosphorane (7) doubly coordinated to Pd via the S− and through a bridging methoxide linked to P and Pd. Attempts to identify the existence of the phosphorane by 31P NMR in a d4-methanol solution containing 10 mM each of 3, trimethyl phosphorothioate (a very slow cleaving substrate), and methoxide proved unsuccessful, instead showing that the phosphorothioate was slowly converted to trimethyl phosphate, with the palladacycle decomposing to Pd0 and free pyridine. These results provide the first reported example where a palladacycle-promoted solvolysis reaction exhibits a break in the Brønsted plot signifying at least one intermediate, while the DFT calculations provide further insight into a more complex mechanism involving two intermediates.