Substituent Effects on the [N-I-N](+) Halogen Bond.

We have investigated the influence of electron density on the three-center [N-I-N](+) halogen bond. A series of [bis(pyridine)iodine](+) and [1,2-bis((pyridine-2-ylethynyl)benzene)iodine](+) BF4(-) complexes substituted with electron withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied by spectroscopic and computational methods. The systematic change of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F, Me, OMe, NMe2) was confirmed by (15)N NMR and by computation of the natural atomic population and the π electron population of the nitrogen atoms. Formation of the [N-I-N](+) halogen bond resulted in >100 ppm (15)N NMR coordination shifts. Substituent effects on the (15)N NMR chemical shift are governed by the π population rather than the total electron population at the nitrogens. Isotopic perturbation of equilibrium NMR studies along with computation on the DFT level indicate that all studied systems possess static, symmetric [N-I-N](+) halogen bonds, independent of their electron density. This was further confirmed by single crystal X-ray diffraction data of 4-substituted [bis(pyridine)iodine](+) complexes. An increased electron density of the halogen bond acceptor stabilizes the [N···I···N](+) bond, whereas electron deficiency reduces the stability of the complexes, as demonstrated by UV-kinetics and computation. In contrast, the N-I bond length is virtually unaffected by changes of the electron density. The understanding of electronic effects on the [N-X-N](+) halogen bond is expected to provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen](+)-type synthetic reagents.

Cu(II)-promoted methanolysis of N,N-bis(2-picolyl)carbamates: rate-limiting metal ion delivery of coordinated alcoholate nucleophile followed by fast partitioning of a tetrahedral intermediate.

Five O-aryl/alkyl N,N-bis(2-picolyl)carbamates were prepared with the O-aryl/alkyl portions being p-nitrophenoxy, m-nitrophenoxy, trifluoroethoxy, methoxy, and isopropoxy (4a,b,c,d,e, respectively) and the kinetics and reaction products of their methanolysis reactions in the presence of Cu(O3SCF3)2 determined. The catalyzed reactions have maximal rates for each substrate at a 1:1 ratio of [4]:[Cu²âº] at (s)(s)pH 7.9, where the active forms are Cu(II):4:(⁻OCH3). The reactions are fast, that for the complex of 4a having a t(1/2) of 30 s. The products of the reaction with 4a and 4b arise exclusively from C-OAr cleavage: those with 4d and 4e arise exclusively from C-N cleavage. With 4c, products from both C-O and C-N cleavage are observed in a 2.17:1 ratio. The common mechanism involves rate-limiting delivery of a Cu(II)-coordinated methoxide to the C═O unit to form a tetrahedral intermediate followed by fast partitioning to products by two pathways with relative barriers dependent on the (s)(s)pK(a)(HOAr/HOR). The data allow one to predict an effective (s)(s)pK(a) of ∼15.6 for the (s)(s)pK(a)(NH) of Cu(II):bis(2-picolyl)amine.

Cu(II)-ion-catalyzed solvolysis of N,N-bis(2-picolyl)ureas in alcohol solvents: evidence for cleavage involving nucleophilic addition and strong assistance of bis(2-picolyl)amine leaving group departure.

The kinetics and products for solvolysis of N-p-nitrophenyl-N',N'-bis(pyridin-2-ylmethyl) urea (7a), N-methyl-N-p-nitrophenyl-N',N'-bis(pyridin-2-yl methyl) urea (7b), and N-phenyl-N',N'-bis(pyridin-2-yl-methyl) urea (DPPU) (7c) promoted by Cu(II) ion in methanol and ethanol were studied under (s)(s)pH-controlled conditions at 25 °C. Methanolysis and ethanolysis of these substrates proceeds rapidly at a 1:1 ratio of substrate:metal ion, the half-times for decomposition of the Cu(II):7a complexes being ~150 min in methanol and 15 min in ethanol. In all cases, the reaction products are the Cu(II) complex of bis(2-picolyl)amine and the O-methyl or O-ethyl carbamate of the parent aniline, signifying that the point of cleavage is the bis(2-picolyl)-N-C=O bond. Reactions of the Cu(II):7b complexes in each solvent proceed about 3-5 times slower than their respective Cu(II):7a complexes, excluding an elimination mechanism that proceeds through an isocyanate which subsequently adds alcohol to give the observed products. The reactions also proceed in other solvents, with the order of reactivity ethanol > methanol >1-propanol >2-propanol > acetonitrile (with 0.2% methanol) > water spanning a range of 150-fold. The mechanism of the reactions is discussed, and the reactivity and mode of cleavage are compared with that of the M(II)-promoted ethanolytic cleavage of a mono-2-picolyl derivative, N-p-nitrophenyl-N'-(pyridin-2-yl-methyl) urea (4a), which had previously been shown to cleave at the aniline N-C=O bond. The large estimated acceleration of the rate of attack of ethoxide on 7b of at least 2 × 10¹6 provided by associating Cu(II) with the departing group in this urea is discussed in terms of a trifunctional role for the metal ion involving Lewis acid activation of the substrate, intramolecular delivery of a Cu(II)-coordinated ethoxide, and metal-ion-assisted leaving group departure.

Rapid Ni, Zn, and Cu ion-promoted alcoholysis of N,N-bis(2-picolyl)- and N,N-bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamides in methanol and ethanol.

The methanolysis and ethanolysis of the Ni(II), Zn(II), and Cu(II) complexes of N,N-bis(2-picolyl)-p-nitrobenzamide (1) and N,N-bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamide (2) were studied under pH-controlled conditions at 25 °C. Details of the mechanism were obtained from plots of the kobs values for the reaction under pseudo-first-order conditions as a function of [M2+]. Such plots give saturation kinetics for the Cu(II)-promoted reactions of 1 and 2 in both solvents, the Zn(II)-promoted reaction of 1 in methanol, and the Zn(II)- and Ni(II)-promoted reactions of 2 in methanol and ethanol. Logs of the maximal observed rate constants obtained from the latter plots, (kobs(max)), when plotted versus s(s)pH, are curved downward only for the Cu(II) complexes of 1 and 2 in both solvents and the Zn(II) complex of 1 in methanol. Despite differences in the metal-binding abilities and pKa values for formation of the active form, there is a common reaction mechanism, with the active form being 1:M(II):(­OR) and 2:M(II):(­OR), where M(II):(­OR) is the metal-bound alkoxide. The acceleration provided by the metal ion is substantial, being 10(14)­10(19) relative to the k2(¯OMe) value for the alkoxide-promoted alcoholysis of the uncomplexed amide.

Cu(II)-promoted methanolysis of N,N-dipicolylacetamide. multistep activation by decoupling of > ̈̈N-C═O resonance via Cu(II)-N binding, delivery of the Cu(II):((-)OCH3) nucleophile, and metal ion assistance of the departure of the leaving group.

The methanolysis of the Cu(II) complex of N-acetyl-N,N-bis(2-picolyl)amine (2) was investigated by a kinetic study as a function of pH in methanol at 25 °C and computationally by DFT calculations. The active species is the basic form of the complex (3(-)), or (1:Cu(II))((-)OCH(3))(HOCH(3))), and the rate constant for its solvolysis is k(max) = 1.5 × 10(-4) s(-1). The mechanism involves Cu(II) binding to the amide N lone pair, decoupling it from >N-C═O resonance, concomitant with Cu(II):((-)OCH(3)) delivery to the adjacent >N-C═O unit, followed by Cu(II)-assisted departure of the N,N-bis(2-picolyl)amide from a tetrahedral intermediate.

Trifunctional metal ion-catalyzed solvolysis: Cu(II)-promoted methanolysis of N,N-bis(2-picolyl) benzamides involves unusual Lewis acid activation of substrate, delivery of coordinated nucleophile, powerful assistance of the leaving group departure.

The methanolyses of Cu(II) complexes of a series of N,N-bis(2-picolyl) benzamides (4a-g) bearing substituents X on the aromatic ring were studied under (s)(s)pH-controlled conditions at 25 °C. The active form of the complexes at neutral (s)(s)pH has a stoichiometry of 4:Cu(II):((-)OCH(3))(HOCH(3)) and decomposes unimolecularly with a rate constant k(x). A Hammett plot of log(k(x)) vs σ(x) values has a ρ(x) of 0.80 ± 0.05. Solvent deuterium kinetic isotope effects of 1.12 and 1.20 were determined for decomposition of the 4-nitro and 4-methoxy derivatives, 4b:Cu(II):((-)OCH(3))(HOCH(3)) and 4g:Cu(II):((-)OCH(3))(HOCH(3)), in the plateau region of the (s)(s)pH/log(k(x)) profiles in both CH(3)OH and CH(3)OD. Activation parameters for decomposition of these complexes are ΔH(++) = 19.1 and 21.3 kcal mol(-1) respectively and ΔS(++) = -5.1 and -2 cal K(-1) mol(-1). Density functional theory (DFT) calculations for the reactions of the Cu(II):((-)OCH(3))(HOCH(3)) complexes of 4a,b and g (4a, X = 3,5-dinitro) were conducted to probe the relative transition state energies and geometries of the different states. The experimental and computational data support a mechanism where the metal ion is coordinated to the N,N-bis(2-picolyl) amide unit and positioned so that it permits delivery of a coordinated Cu(II):((-)OCH(3)) nucleophile to the C═O in the rate-limiting transition state (TS) of the reaction. This proceeds to a tetrahedral intermediate INT, occupying a shallow minimum on the free energy surface with the Cu(II) coordinated to both the methoxide and the amidic N. Breakdown of INT is a virtually barrierless process, involving a Cu(II)-assisted departure of the bis(2-picolyl)amide anion. The analysis of the data points to a trifunctional role for the metal ion in the solvolysis mechanism where it activates intramolecular nucleophilic attack on the C═O group by coordination to an amidic N in the first step of the reaction and subsequently assists leaving group departure in the second step. The catalysis is very large; compared with the second order rate constant for methoxide attack on 4b, the computed reaction of CH3O(-) and 4b:Cu(II):(HOCH(3))(2) is accelerated by roughly 2.0 × 10(16) times.

Solvent induced cooperativity of Zn(II) complexes cleaving a phosphate diester RNA analog in methanol.

The kinetics of cyclization of 2-hydroxypropyl p-nitrophenyl phosphate (1) promoted by two mononuclear Zn(II) catalytic complexes of bis(2-pyridylmethyl)benzylamine (4) and bis(2-methyl 6-pyridylmethyl)benzylamine (5) in methanol were studied under (s)(s)pH-controlled conditions (where (s)(s)pH refers to [H(+)] activity in methanol). Potentiometric titrations of the ligands in the absence and presence of Zn(2+) and a non-reactive model for 1 (2-hydroxylpropyl isopropyl phosphate (HPIPP, 6)) indicate that the phosphate is bound tightly to the 4:Zn(II) and 5:Zn(II) complexes as L:Zn(II):6(-), and that each of these undergoes an additional ionization to produce L:Zn(II):6(-):((-)OCH(3)) or a bound deprotonated form of the phosphate, L:Zn(II):6(2-). Kinetic studies as a function of [L:Zn(II)] indicate that the rate is linear in [L:Zn(II)] at concentrations well above those required for complete binding of the substrate. Plots of the second order rate constants (defined as the gradient of the rate constant vs. [complex] plot) vs. (s)(s)pH in methanol are bell-shaped with rate maxima of 23 dm mol(-1) s(-1) and 146 dm mol(-1) s(-1) for 4:Zn(II) and 5:Zn(II), respectively, at their (s)(s)pH maxima of 10.5 and 10. A mechanism is proposed that involves binding of one molecule of complex to the phosphate to yield a poorly reactive 1 : 1 complex, which associates with a second molecule of complex to produce a transient cooperative 2 : 1 complex within which the cyclization of 1 is rapid. The observations support an effect of the reduced polarity solvent that encourages the cooperative association of phosphate and two independent mononuclear complexes to give a reactive entity.

Methanolysis of thioamide promoted by a simple palladacycle is accelerated by 10(8) over the methoxide-catalyzed reaction.

Palladacycle 1 catalyzes the methanolytic cleavage of N-methyl-N-(4-nitrophenyl)thiobenzamide (4) via a mechanism involving formation of a Pd-bound tetrahedral intermediate (TI). The rate constant for decomposition of the complex formed between 1, methoxide, and 4 is 9.3 s(-1) at 25 °C; this reaction produces methyl thiobenzoate and N-methyl-4-nitroaniline. The ratio of the second-order rate constant for the catalyzed reaction, given as k(cat)/K(d), relative to that of the methoxide-promoted reaction is 3 × 10(8), representing a very large catalysis of thioamide bond cleavage by a synthetic metal complex.

Study on the transesterification of methyl aryl phosphorothioates in methanol promoted by Cd(II), Mn(II), and a synthetic Pd(II) complex.

Methanol solutions containing Cd(II), Mn(II), and a palladacycle, (dimethanol bis(N,N-dimethylbenzylamine-2C,N)palladium(II) (3), are shown to promote the methanolytic transesterification of O-methyl O-4-nitrophenyl phosphorothioate (2b) at 25 °C with impressive rate accelerations of 10(6)-10(11) over the background methoxide promoted reaction. A detailed mechanistic investigation of the methanolytic cleavage of 2a-d having various leaving group aryl substitutions, and particularly the 4-nitrophenyl derivative (2b), catalyzed by Pd-complex 3 is presented. Plots of k(obs) versus palladacycle [3] demonstrate strong saturation binding to form 2b:3. Numerical fits of the kinetic data to a universal binding equation provide binding constants, K(b), and first order catalytic rate constants for the methanolysis reaction of the 2b:3 complex (k(cat)) which, when corrected for buffer effects, give corrected (k(cat)(corr)) rate constants. A sigmoidal shaped plot of log(k(cat)(corr)) versus (s)(s)pH (in methanol) for the cleavage of 2b displays a broad (s)(s)pH independent region from 5.6 ≤ (s)(s)pH ≤ 10 with a k(minimum) = (1.45 ± 0.24) × 10(-2) s(-1) and a [lyoxide] dependent wing plateauing above a kinetically determined (s)(s)pK(a) of 12.71 ± 0.17 to give a k(maximum) = 7.1 ± 1.7 s(-1). Brønsted plots were constructed for reaction of 2a-d at (s)(s)pH 8.7 and 14.1, corresponding to reaction in the midpoints of the low and high (s)(s)pH plateaus. The Brønsted coefficients (ß(LG)) are computed as -0.01 ± 0.03 and -0.86 ± 0.004 at low and high (s)(s)pH, respectively. In the low (s)(s)pH plateau, and under conditions of saturating 3, a solvent deuterium kinetic isotope effect of k(H)/k(D) = 1.17 ± 0.08 is observed; activation parameters (ΔH(Pd)(++) = 14.0 ± 0.6 kcal/mol and ΔS(Pd)(++)= -20 ± 2 cal/mol·K) were obtained for the 3-catalyzed cleavage reaction of 2b. Possible mechanisms are discussed for the reactions catalyzed by 3 at low and high sspH. This catalytic system is shown to promote the methanolytic cleavage of O,O-dimethyl phosphorothioate in CD3OD, producing (CD3O)2P═O(S(-)) with a half time for reaction of 34 min.

Palladacycle-promoted solvolytic cleavage of O,O-dimethyl O-aryl phosphorothioates. Converting a phosphorane-like transition state to an observable intermediate.

The mechanism of cleavage of a series of seven O,O-dimethyl O-aryl phosphorothioates (6a-g) promoted by a C,N-palladacycle, (2-[N,N-dimethylamino(methyl)phenyl]-C(1),N)(pyridine) palladium(II) triflate (5:OTf) in methanol at 25 °C was investigated with the aim of identifying catalytically important intermediates. Complete (s)(s)pH/rate profiles (in methanol) were conducted for the cleavage of 6a-g in the presence of 0.08 mM 5. The log k(obs) for the catalyzed methanolysis of 6a increases linearly with (s)(s)pH with a plateau above the (s)(s)pK(a)(1) of 11.16 for formation of 5:(-)OCH3. The profiles for 6b-g are bell-shaped, depending on the apparent ionizations of two acidic groups, with the rate constant maximum of the bell and the (s)(s)pK(a)(1) values shifting to higher (s)(s)pH values as the (s)(s)pK(a)(HOAr) of the leaving group phenol increases. A Brønsted plot of the log k(obs)(max) (the maximum rate constants for cleavage of 6a-g) vs (s)(s)pK(a)(HOAr) exhibits a downward break at ~ (s)(s)pK(a)(HOAr) 13, with the two wings having ß(lg) values of 0.01 and -0.96. A model describing the kinetically important species involves a complex series of equilibria: 5:(HOCH(3)):pyr <=> 5:((-)OCH3):pyr + H(+) <=>(6) 5:((-)OCH3):6 + pyr <=> phosphorane 7 → product, where the rate limiting steps change from formation of 5:((-)OCH3):6 to formation of thiophosphorane 7 and then to product formation as the aryloxy leaving groups of 6 get progressively worse. Kinetic experiments indicate that the reaction of 5 with 6e, having a 4-chlorophenoxy leaving group, rapidly produces a transient intermediate, postulated to be the palladacycle-bound 5-coordinate thiophosphorane (7e) that exists long enough to obtain its UV/vis spectrum by stopped-flow spectrophotometry. Detailed analysis of the data sheds light on the origins of a previously reported anomalously large ß(lg) of -1.93 for the descending wing of a Brønsted plot (J. Am. Chem. Soc. 2010, 132, 16599). Finally, energetics analysis indicates that the binding of palladacycle to the transition state comprising attack of methoxide on 6e, [MeO(-) + 6e](++), stabilizes the latter by 34.9 kcal/mol, converting that transition state into an observable intermediate.

Demonstration of prominent Cu(II)-promoted leaving group stabilization of the cleavage of a homologous set of phosphate mono-, di-, and triesters in methanol.

A series of phosphate mono-, di-, and triesters with a common leaving group (LG) (2'-(2-phenoxy)-1,10-phenanthroline) was prepared, and the kinetics of decomposition of their Cu(II) complexes was studied in methanol at 25 degrees C under (s)(s)pH-controlled conditions. The Cu(II) complexes of 2-[2'-phenanthrolyl]phenyl phosphate (Cu(II):6), 2-[2'-phenanthrolyl]phenyl methyl phosphate (Cu(II):7), and 2-[2'-phenanthrolyl]phenyl dimethyl phosphate (Cu(II):8) are tightly bound, having dissociation constants Kd < or = 3 x 10(-7) M, with the Cu(II) being in contact with the departing phenoxide. The (s)(s)pH/rate profile for cleavage of Cu(II):6 has a low (s)(s)pH plateau (k(o) = 6.3 x 10(-3) s(-1)), followed by a bell-shaped maximum (kcat(max) = 14.7 +/- 0.4 s(-1)) dependent on two ionizations with (s)(s)pKa(2) and (s)(s)pKa(3) = 7.8 +/- 0.1 and 11.8 +/- 0.2. The (s)(s)pH/rate profile for cleavage of Cu(II):7 has a broad plateau from (s)(s)pH 3 to (s)(s)pH 10 followed by a descending wing at higher (s)(s)pH with a gradient of -2. The (s)(s)pH/rate profile for cleavage of Cu(II):8 is sigmoidal with two plateaus (k1 = (2.0 +/- 0.2) x 10(-5) s(-1), k2 = (1.2 +/- 0.2) x 10(-6) s(-1)), connected by an ionization with a (s)(s)pKa of 6.03. Activation parameters are given for the reactions in the plateau regions: all three species show similar DeltaH(double dagger) terms of 21.4-21.6 kcal/mol, with major differences in the DeltaS(double dagger) terms, which vary from 18 to 2.3 to -7.4 cal/(mol x K) passing from the mono- to di- to triester. Detailed analyses of the kinetics indicate that the reactions involve spontaneous solvent-mediated cleavage of the Cu(II)-coordinated phosphate dianion [Cu(II):6b]0 and phosphate diester monoanion [Cu(II):7b]+ and, for the triester, complexes containing Cu(II) and Cu(II):(-)OCH3 designated as [Cu(II):8a]2+ and [Cu(II):8b]+. Reactions where methoxide is the active nucleophile are not observed. Comparisons of the rates of the decomposition of these species at their (s)(s)pH maxima in the neutral (s)(s)pH region with the estimated rates of the background reactions indicate that leaving group assistance provided by the coordinated Cu(II) accelerates the cleavage of the phosphate mono-, di-, and triesters by 10(14) to 10(15), 10(14), and 10(5). Detailed Hyperquad 2000 analysis of titration data indicates that phenoxide 9- is bound 23 kcal/mol stronger than the phosphate triester 8. It is the realization of part of this energy in the emerging products resulting from P-O(LG) cleavage that provides the driving force for the catalyzed 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 ßlg = −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 ßlg 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.

On the question of stepwise vs. concerted cleavage of RNA models promoted by a synthetic dinuclear Zn(II) complex in methanol: implementation of a noncleavable phosphonate probe.

To address the question of concerted versus a stepwise reaction mechanisms for the cyclization of the 2-hydroxypropyl aryl and alkyl RNA models (1a-k) promoted by dinuclear Zn(II) complex (4) at (s)spH 9.8 and 25 degrees C, the non-cleavable O-hydroxypropyl phenylphosphonate analogues 6a and 6b were subjected to the catalytic reaction in methanol. These phosphonates did not undergo isomerization in the study, the only observable methanolysis reaction being release of 1,2-propanediol and the formation of O-methyl phenylphosphonate. The observed first order rate constants for methanolysis promoted by 4 are k(obs)(6a) = (1.47 +/- 0.09) x 10(-4) s(-1) and k(obs)(6b) = (2.08 +/- 0.09) x 10(-6) s(-1), respectively. The rates of methanolysis of a series of O-aryl phenylphosphonates (8a-f) in the presence of increasing [4] were analyzed to provide binding constants, Kb, and the catalytic rate constant, kcat(max), for the unimolecular decomposition of the 8:4 Michaelis complex. A Brønsted plot of the log (k(cat)(max)) vs. sspKa(phenol) (acidity constant of the conjugate acid of the leaving group in methanol) was fitted to a linear regression of log kcat(max) = (-0.80 +/- 0.07)(s)spKa + (10.2 +/- 1.0) which includes the datum for 6a. The datum for 6b, which reacts approximately 70-fold slower, falls significantly below the linear correlation. The data provide additional evidence consistent with a concerted cyclization of RNA models 1a-k promoted by 4.

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.

Dinuclear Zn(II) complex promotes cleavage and isomerization of 2-hydroxypropyl alkyl phosphates by a common cyclic phosphate intermediate.

The kinetics and cleavage products of 2-hydroxypropyl p-nitrophenyl phosphate were determined in methanol containing the di-Zn(II) complex of bis-1,3-N1,N1'-(1,5,9-triazacyclododecyl)propane (4). Time-dependent 1H NMR spectra of the reaction mixture at sspH 9.8 +/- 0.1 show that the catalytic reaction proceeds via a cyclic phosphate (4-methylethylene phosphate, 2) that is subsequently cleaved into a kinetic mixture of two isomeric products, 2-hydroxypropyl methyl phosphate (3) and 1-hydroxypropan-2-yl methyl phosphate (3a), in a 29/71 ratio. In the presence of 4, the kinetic mixture of 3/3a is transformed into a thermodynamic mixture of 72/28 3/3a. The time-dependent 1H NMR spectra of 4 and a 22/78 mixture of 3/3a in CD3OH show that the formation of the thermodynamic mixture occurs on the same time scale as replacement of the P-OCH3 group of the 3/3a starting materials with OCD3. Detailed kinetic studies indicate that the dominant process for loss of the OCH3 group and equilibration of 3/3a is via a 4-catalyzed process where each of the isomers cyclizes to methylethylene phosphate (2), which subsequently reforms the 3/3a thermodynamic mixture. The kcatmax for 4-catalyzed cyclization of 3 and three other 2-hydroxypropyl O-alkyl phosphates (alkyl = CF3CH2- (6a), CH2FCH2- (6b), and CH3CH2- (6c)) has been determined, and the Brønsted plot comprising the log kcatmax vs leaving group sspKa that includes several previously studied 2-hydroxypropyl aryl phosphates is linear, following the expression log kcatmax = (-0.85 +/- 0.02) sspKa + (12.8 +/- 0.4). The betalg value of -0.85 suggests that the catalyzed cleavage of the P-OAr/OR bond has progressed to about 45% in the transition state. The combined results are analyzed in terms of two possible processes involving either a concerted reaction leading to the cyclic phosphate 2 from which the thermodynamic mixture of 3/3a is formed or a stepwise one involving a transient phosphorane whose predominant fate is to eliminate methoxide and proceed to 2 rather than partitioning between 3, 3a, and 2.

An immobilized ortho-palladated dimethylbenzylamine complex as an efficient catalyst for the methanolysis of phosphorothionate pesticides.

The methanolysis of a series of P=S phosphorothionate pesticides (fenitrothion, coumaphos, diazinon, and dichlofenthion) catalyzed by an ortho-palladated complex covalently attached to two different solid supports, macroporous polystyrene and amorphous silica gel, was studied. Both the polystyrene and the silica-based catalysts showed excellent activity in methanol near neutral pH (neutral s(s)pH = 8.38) at ambient temperature. These heterogeneous catalysts can be readily recovered and reused without significant loss of activity. Fifty milligrams of the silica-supported catalyst SiPd1 offered an acceleration of up to 8.6 x 10(9)-fold for the methanolysis of fenitrothion (2) over the methoxide-promoted background reaction at s(s)pH = 8.8. For the same reaction, 50 mg of polystyrene-supported complex PSPd2 provided a 3.7 x 10(9)-fold acceleration at s(s)pH = 8.8. When accounting for the amount of palladium in the solid, the slight superiority of silica over polystyrene as a solid support is believed to be a result of several possible factors including a higher concentration of active sites accessible to the reaction solvent and a more hydrophilic surface environment that allows better interaction of the methanol solvent with the attached palladacycle. Unlike the behavior in homogeneous solution, the rate of methanolysis of the substrates catalyzed by the solid catalysts was relatively insensitive to the nature of the substrate, probably indicating that a mass transport process is rate limiting. The solid-supported materials effectively decompose malathion at roughly stoichiometric ratios, but they are strongly inhibited by the thiol product resulting from the cleavage of the P=S(SR) linkage.

Investigation of the effect of oxy bridging groups in dinuclear Zn(II) complexes that catalyze the cleavage of a simple phosphate diester RNA analogue.

Two sets of dinuclear Zn(II) complexes were prepared to determine the effect of the presence of oxyanionic bridging groups between the metal centers on the catalytic activity toward the methanolysis of the RNA analogue 2-hydroxypropyl-4-nitrophenyl phosphate (HPNPP, 2). The Zn(II)2 complexes of bis(di-(2-pyridylmethyl)amino)-m-xylene (6) and 2,6-bis(di-(2-pyridylmethyl)amino)-4-methylphenol (7) were compared to assess the effect of a bridging phenoxide ligand, while the Zn(II)2 complex of 1,3-bis-N1-(1,5,9-triazacyclododecyl)-propan-2-ol (8) was prepared to determine the effect of the 2-propoxy group compared to the previously studied complex of 1,3-bis-N1-(1,5,9-triazacyclododecyl)-propane (4). Detailed kinetic studies of the cleavage of 2 including k(obs) vs [catalyst] plots and (s)(s)pH-rate profiles were performed for each system along with potentiometric titration experiments to determine the acid dissociation constants for the catalytically relevant groups. The results show that inclusion of the phenoxy bridging group in 7:Zn(II)2 reduces the second-order catalytic rate constant (k2(cat)) for cleavage of 2 by a factor of 160 relative to that of 6:Zn(II)2, while the incorporation of a propoxy group in 8:Zn(II)2 reduces its efficacy by 3.7 x 10(4) times relative to 4:Zn(II)2. Energetics calculations reveal that 6:Zn(II)2 offers a 3.7 kcal/mol greater stabilization of the reaction transition state for the cleavage of 2 than does 7:Zn(II)2 and that 4:Zn(II)2 affords 6.5 kcal/mol greater transition state stabilization than does 8:Zn(II)2. The analyses show that the reduction in the transition state stabilization experienced with the complexes having permanently bridging oxyanion groups stems almost entirely from a weaker binding of the phosphate and catalyst, and a reduced catalytic rate constant. These results indicate that the presence of a bridging oxyanion ligand between the metal centers, a common structural element required for the successful formation of many small molecule dinuclear catalysts that show cooperative activity in water, significantly impairs the catalytic efficiency for cleavage of 2.

Enzyme-like acceleration for the hydrolysis of a DNA model promoted by a dinuclear Zn(II) catalyst in dilute aqueous ethanol.

The rates and products of cleavage of methyl (2-chloro-4-nitrophenyl) phosphate (2) promoted by a dinuclear Zn(II) complex (3) of 1,3-bis-N,N'(1,5,9-triazacyclododecyl)propane along with 1 equiv of ethoxide were investigated in ethanol solution containing small amounts of water (8 mM or=1.6 x 10(17) times relative to the background hydroxide reaction, suggesting that complex 3 promotes the hydrolysis at least 1000 times more effectively than ethanolysis.

A simple DNase model system comprising a dinuclear Zn(II) complex in methanol accelerates the cleavage of a series of methyl aryl phosphate diesters by 10(11)-10(13).

The di-Zn(II) complex of 1,3-bis[ N1, N1'-(1,5,9-triazacyclododecyl)]propane with an associated methoxide ( 3:Zn(II) 2: (-)OCH 3) was prepared and its catalysis of the methanolysis of a series of fourteen methyl aryl phosphate diesters ( 6) was studied at s (s)pH 9.8 in methanol at 25.0 +/- 0.1 degrees C. Plots of k obs vs [ 3:Zn(II) 2: (-)OCH 3] free for all members of 6 show saturation behavior from which K(M) and kcat (max) were determined. The second order rate constants for the catalyzed reactions (kcat (max)/K(M)) for each substrate are larger than the corresponding methoxide catalyzed reaction (k 2 (-OMe)) by 1.4 x 10(8) to 3 x 10 (9)-fold. The values of k cat (max) for all members of 6 are between 4 x 10(11) and 3 x 10(13) times larger than the solution reaction at s (s)pH 9.8, with the largest accelerations being given for substrates where the departing aryloxy unit contains ortho-NO 2 or C(O)OCH 3 groups. Based on the linear Brønsted plots of k cat (max) vs s (s)pKa of the phenol, beta lg values of -0.57 and -0.34 are determined respectively for the catalyzed methanolysis of "regular" substrates that do not contain the ortho-NO 2 or C(O)OCH 3 groups, and those substrates that do. The data are consistent with a two step mechanism for the catalyzed reaction with rate limiting formation of a catalyst-coordinated phosphorane intermediate, followed by fast loss of the aryloxy leaving group. A detailed energetics calculation indicates that the catalyst binds the transition state comprising [CH 3O (-): 6], giving a hypothetical [ 3:Zn(II) 2:CH 3O (-): 6] complex, by -21.4 to -24.5 kcal/mol, with the strongest binding being for those substrates having the ortho-NO 2 or C(O)OCH 3 groups.

The dinuclear Zn(II) complex catalyzed cyclization of a series of 2-hydroxypropyl aryl phosphate RNA models: progressive change in mechanism from rate-limiting P-O bond cleavage to substrate binding.

A methoxide-bridged dinuclear Zn(II) complex of 1,3-[N,N'-bis(1,5,9-triazacyclododecane)]propane (1-Zn(II)2:(-OCH3)) was prepared, and its catalysis of the cyclization of a series of 2-hydroxypropyl aryl phosphates (4a-g) was investigated in methanol at pH 9.8, T = 25degreesC by stopped-flow spectrophotometry. An X-ray diffraction structure of the hydroxide analogue of 1-Zn(II)2:(-OCH3), namely 1-Zn(II)2:(-OH), reveals that each of the Zn(II) ions is coordinated by the three N's of the triazacyclododecane units and a bridging hydroxide. The cyclizations of substrates 4a-g reveal a progressive change in the observed kinetics from Michaelis-Menten saturation kinetics for the poorer substrates (4-OCH3 (4g); 4-H (4f); 3-OCH3 (4e); 4-Cl (4d); 3-NO2, (4c)) to second-order kinetics (linear in 1-Zn(II)2:(-OCH3)) for the better substrates (4-NO2,3-CH3 (4b); 4-NO2, (4a)). The data are analyzed in terms of a multistep process whereby a first formed complex rearranges to a reactive complex with a doubly activated phosphate coordinated to both metal ions. The kinetic behavior of the series is analyzed in terms of change in rate-limiting step for the catalyzed reaction whereby the rate-limiting step for the poorer substrates (4g-c) is the chemical step of cyclization of the substrate, while for the better substrates (4b,a) the rate-limiting step is binding. The catalysis of the cyclization of these substrates is extremely efficient. The kcat/KM values for the catalyzed reactions range from 2.75 x 10(5) to 2.3 x 10(4) M-1 s-1, providing an acceleration of 1 x 10(8) to 4 x 10(9) relative to the methoxide reaction (k2OCH3, which ranges from 2.6 x 10(-3) to 5.9 x 10(-6) M-1 s-1 for 4a-g). At a pH of 9.8 where the catalyst is maximally active, the acceleration for the substrates ranges from (1 - 4) x 10(12) relative to the background reaction at the same pH. Detailed energetics calculations show that the transition state for the catalyzed reaction comprising 1-Zn(II)2, methoxide, and 4 is stabilized by about -21 to -23 kcal/mol relative to the transition state for the methoxide reaction. The pronounced catalytic activity is attributed to a synergism between a positively charged catalyst that has high affinity for the substrate and for the transition state for cyclization, and a medium effect involving a reduced polarity/dielectric constant that complements a reaction where an oppositely charged reactant and catalyst experience charge dispersal in the transition state.