Aluminosilicate surfaces as promoters for peptide bond formation: an assessment of Bernal's hypothesis by ab initio methods

The role in prebiotic chemistry that Br?nsted and Lewis sites, both present at the surface of common aluminosilicates, may have played in favoring the peptide bond formation has been addressed by ab initio methods within a cluster approach. B3LYP/6-31+G(d,p) free energy potential energy surfaces have been fully characterized for the model reaction glycine + NH3 --> 2-NH2 acetamide (mimicking the true 2 Gly --> GlyGly one) occurring on (i) a Lewis site, (ii) a Br?nsted site, and (iii) a combined action of Lewis/Br?nsted sites. Compared to the gas-phase (gp) activation free energy of 50 kcal/mol, the Lewis site alone reduces the gp barrier to 41 kcal/mol, whereas the activation by the Br?nsted site dramatically reduces the barrier to about 18 kcal/mol. Nevertheless, formation of the prereactant complex in this latter case will rarely occur, since water will easily displace the glycine molecule interacting with the Br?nsted site. However, if a realistic feldspar surface with neighboring Br?nsted and Lewis sites is considered, the proper prereactant complex is highly stabilized by a simultaneous interaction with the Lewis and the Br?nsted sites, in such a way that the Lewis site strongly attaches the glycine molecule to the surface whereas the Br?nsted site efficiently catalyzes the condensation reaction, showing that the interplay between Lewis/Br?nsted sites is an important issue. The free energy barrier computed for the realistic feldspar surface model is 26 kcal/mol. The role of dispersive interactions on the free energy barrier and the stabilization of the final product, not accounted for by the B3LYP functional, have been estimated and shown to be substantial. Speculations about further elongation of the formed dipeptide have been put forward on the basis of the relatively strong interaction energy of the formed GlyGly dipeptide with the aluminosilicate surface.     

Mechanistic consequences of composition in acid catalysis by polyoxometalate keggin clusters

The kinetics and mechanism of ether and alkanol cleavage reactions on Br?nsted acid catalysts based on polyoxometalate (POM) clusters are described in terms of the identity and dynamics of elementary steps and the stability of the transition states involved. Measured rates and theoretical calculations show that the energies of cationic transition states and intermediates depend on the properties of reactants (proton affinity), POM clusters (deprotonation enthalpy), and ion-pairs in transition states or intermediates (stabilization energy). Rate equations and elementary steps were similar for dehydration of alkanols (2-propanol, 1- and 2-butanol, tert-butanol) and cleavage of sec-butyl-methyl ether on POM clusters with different central atoms (P, Si, Co, Al). Dehydration rates depend on the rate constant for elimination from adsorbed alkanols or ethers and on the equilibrium constant for the formation of unreactive reactant dimers. Elimination involves E1 pathways and late carbenium-ion transition states. This is consistent with small kinetic isotope effects for all deuterated alkanols, with strong effects of substituents on elimination rates, and with the similar alkene stereoselectivities measured for alkanol dehydration, ether cleavage, and alkene double-bond isomerization. n-Donor reactants (alkanols, ethers) and products (water) inhibit dehydration rates by forming stable dimers that do not undergo elimination; their stability is consistent with theoretical estimates, with the dynamics of homogeneous analogues, and with the structure and proton affinity of the n-donors. Elimination rate constants increased with increasing valence of the central POM atom, because of a concurrent decrease in deprotonation enthalpies (DPE), which leads to more stable anionic clusters and ion-pairs at transition states. The DPE of POM clusters influences catalytic rates less than the proton affinity of the alkene-like organic moiety at the late carbenium-ion-type transition states involved. These different sensitivities reflect the fact that weaker acids typically form anionic clusters with a higher charge density at the transition state; these clusters stabilize cationic fragments more effectively than those of stronger acids, which form more stable conjugate bases with lower charge densities. These compensation effects are ubiquitous in acid chemistry and also evident for mineral acids. The stabilization energy and the concomitant charge density and distribution in the anion, but not the acid strength (DPE), determine the kinetic tolerance of n-donors and the selectivity of reactions catalyzed by Br?nsted acids.     

A minimalist approach to understanding the efficiency of mononuclear Zn(II) complexes as catalysts of cleavage of an RNA analog

Mononuclear complexes between Zn(2+) and the following four macrocycles were prepared: 1,4,7,10-tetraazacyclododecane (1), 1-oxa-4,7,10-triazacyclododecane (2), 1,5,9-triazacyclododecane (3) and 1-hydroxyethyl-1,4,7-triazacyclononane (4). The pH rate profiles of values of the observed second-order rate constant log (k(Zn))(app) for Zn(X)(OH(2))-catalyzed cleavage (X = 1, 2, 3 and 4) of 2-hydroxypropyl-4-nitrophenyl phosphate (HpPNP) show downward breaks centered at the pK(a) for ionization of the respective zinc bound water. At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between the catalyst and the bound transition state is 5.7, 7.4, 7.4 and 5.9 kcal mol(-1) for the reactions catalyzed by Zn(1)(OH(2)), Zn(2)(OH(2)), Zn(3)(OH(2)) and Zn(4)(OH(2)), respectively. The interactions between the metal cation and the macrocycle cause either a modest increase or reduction in transition state stabilization compared with 6.6 kcal mol(-1) stabilization for catalysis by Zn(OH(2))(6). The best Zn(II)-macrocycle catalysts are those for which the interactions between the metal ion and macrocycle are the weakest. Inhibition studies show that each of the four catalysts form complexes with phosphate and oxalate dianions with a much higher affinity than diethyl phosphate monoanion, consistent with stronger interaction of the catalysts with the transition state dianion compared with the substrate monoanion HpPNP. The pH-dependence of methyl phosphate inhibition of Zn(2) catalyzed cleavage of HpPNP shows that only the Zn(2)(OH(2)) species binds the inhibitor. This result is consistent with a mechanism that has Zn(2)(OH(2)) as the active catalytic species.     

Formation and stability of enolates of acetamide and acetate anion: an Eigen plot for proton transfer at alpha-carbonyl carbon

Second-order rate constants were determined in D(2)O for deprotonation of acetamide, N,N-dimethylacetamide, and acetate anion by deuterioxide ion and for deprotonation of acetamide by quinuclidine. The values of k(B) = 4.8 x 10(-8) M(-1) s(-1) for deprotonation of acetamide by quinuclidine (pK(BH) = 11.5) and k(BH) = 2-5 x 10(9) M(-1) s(-1) for the encounter-limited reverse protonation of the enolate by protonated quinuclidine give pK(a)(C) = 28.4 for ionization of acetamide as a carbon acid. The limiting value of k(HOH) = 1 x 10(11) s(-1) for protonation of the enolate of acetate anion by solvent water and k(HO) = 3.5 x 10(-9) M(-1) s(-1) for deprotonation of acetate anion by HO(-) give pK(a)(C) approximately 33.5 for acetate anion. The change in the rate-limiting step from chemical proton transfer to solvent reorganization results in a downward break in the slope of the plot of log k(HO) against carbon acid pK(a) for deprotonation of a wide range of neutral alpha-carbonyl carbon acids by hydroxide ion, from -0.40 to -1.0. Good estimates are reported for the stabilization of the carbonyl group relative to the enol tautomer by electron donation from alpha-SEt, alpha-OMe, alpha-NH(2), and alpha-O(-) substituents. The alpha-NH(2) and alpha-OMe groups show similar stabilizing interactions with the carbonyl group, while the interaction of alpha-O(-) is only 3.4 kcal/mol more stabilizing than for alpha-OH. We propose that destabilization of the enolate intermediates of enzymatic reactions results in an increasing recruitment of metal ions by the enzyme to provide electrophilic catalysis of enolate formation.     

Polar group enhanced gas-phase acidities of carboxylic acids: an investigation of intramolecular electrostatic interaction

We studied the effects of polar groups on the gas-phase acidities of carboxylic acids experimentally and computationally. In this connection, the gas-phase acidities (DeltaH(acid), the enthalpy of deprotonation, and DeltaG(acid), the deprotonation free energy) of borane-complexed methylaminoacetic acid ((CH(3))2N(BH(3))CH(2)CO(2)H) and methylthioacetic acid (CH(3)S(BH(3))CH(2)CO(2)H) were measured using the kinetic method in a flowing afterglow-triple quadrupole mass spectrometer. The values of DeltaH(acid) and DeltaG(acid) of (CH(3))2N(BH(3))CH(2)CO(2)H were determined to be 328.8 +/- 1.9 and 322.1 +/- 1.9 kcal/mol, and those of CH(3)S(BH(3))CH(2)CO(2)H were determined to be 325.8 +/- 1.9 and 319.2 +/- 1.9 kcal/mol, respectively. The theoretical enthalpies of deprotonation of (CH(3))2N(BH(3))CH(2)CO(2)H (329.2 kcal/mol) and CH(3)S(BH(3))CH(2)CO(2)H (325.5 kcal/mol) were calculated at the B3LYP/6-31+G(d) level of theory. The calculated enthalpies of deprotonation of N-oxide-acetic acid (CH(3)NOCH(2)CO(2)H, 329.4 kcal/mol) and S-oxide-acetic acid (CH(3)SOCH(2)CO(2)H, 328.6 kcal/mol) are comparable to the experimental results for borane-complexed methylamino- and methylthioacetic acids. The enthalpy of deprotonation of sulfone-acetic acid (CH(3)SO2CH(2)CO(2)H, 326.1 kcal/mol) is about 2 kcal/mol lower than the S-oxide-acetic acid. The calculated enthalpy of deprotonation of sulfoniumacetic acid, (CH(3))2S+CH(2)CO(2)H, is 243.0 kcal/mol. Compared to the corresponding reference molecules, CH(3)NHCH(2)CO(2)H and CH(3)SCH(2)CO(2)H, the dipolar group and the monopolar group substituted carboxylic acids are stronger acids by 11-14 and 97 kcal/mol, respectively. We correlated the changes of the acidity upon a polar group substitution to the electrostatic free energy within the carboxylate anion. The acidity enhancements in polar group substituted carboxylic acids are the results of the favorable electrostatic interactions between the polar group and the developing charge at the carboxyl group.     

Electronic Factors Influencing the Decarboxylation of beta-Keto Acids. A Model Enzyme Study

A theoretical study of the mechanism of decarboxylation of beta-keto acids is described. A cyclic transition structure was found with essentially complete proton transfer from the carboxylic acid to the beta-carbonyl group. The activation barrier for decarboxylation of formylacetic acid is predicted to be 28.6 kcal/mol (MP4SDTQ/6-31G//MP2/6-31G) while loss of CO(2) from its anion exhibits a barrier of only 20.6 kcal/mol (MP4SDTQ/6-31+G//MP2/6-31+G). Barrier heights of decarboxylation of malonic acid and alpha,alpha-dimethylacetoacetic acid are predicted to be 33.2 and 26.7 kcal/mol, respectively. Model enzyme studies using a thio methyl ester of malonate anion suggests that the role of malonyl-CoA is to afford a polarizable sulfur atom to stabilize the developing enolate anion in the transition structure for decarboxylation. Adjacent positively charged ammonium ions are also observed to stabilize the loss of CO(2) from a carboxylate anion by through-bond Coulombic stabilization of the transition structure.     

Hydrogen-shift isomerism: mass spectrometry of isomeric benzenesulfonate and 2-, 3- and 4-dehydrobenzenesulfonic acid anions in the gas phase

The isomeric 3- and 4-dehydrobenzenesulfonic acid anions b and c were prepared by collision induced dissociation (CID) of the [M - H](-) ions of isomeric sulfobenzoic acids obtained by negative electrospray ionization (ESI). The CID spectra (MS(3)) of anions b and c are different from each other, and both are different from that of the isomeric benzenesulfonate anion a, obtained from benzenesulfonic acid. The stability of ions b and c shows that 1,2-proton transfer does not take place in this system under the conditions of the CID experiment. Density functional (DFT) calculations at B3LYP/6-31+G(2d,p) level of theory show that benzenesulfonate anion a is the most stable isomer, and the energies of isomers b and c are higher by more than 65 kcal mol(-1). The calculated energies of the transition states involved in the 1,2-hydrogen migration leading to the interconversion of the isomeric anions are very high (>120 kcal mol(-1)relative to ion a, barrier energies >55 kcal mol(-1)), much higher than those of transition structures leading to fragmentation. This situation does not allow isomerization of ions b and c to a, under the conditions of the CID experiments. The isomeric 2-dehydrobenzenesulfonic acid anion isomerizes to the benzenesulfonate anion a by a facile proton transfer from the SO(3)H group to the adjacent position 2. The results of this work indicate that the gas phase deprotonation of meta- and para-sulfobenzoic acids is a kinetically controlled process.     

Brønsted base-modulated regioselectivity in the aerobic oxidative amination of styrene catalyzed by palladium

Palladium(II)-catalyzed aerobic oxidative amination of styrene with oxazolidinone proceeds with catalyst-controlled regioselectivity: (CH3CN)2PdCl2 (1) and (Et3N)2PdCl2 (2) catalyze formation of the anti-Markovnikov and Markovnikov enecarbamate products, 3 and 4, respectively. Kinetic studies and deuterium kinetic isotope effects demonstrate that these two reactions possess different rate-limiting steps, and the data indicate that the product regiochemistry arises from the presence or absence of an effective Br?nsted base in the reaction. In the presence of a Br?nsted base such as triethylamine or acetate, the kinetically preferred Markovnikov aminopalladation adduct of styrene is trapped via rapid deprotonation of a zwitterionic intermediate and leads to formation of 4. In the absence of an effective Br?nsted base, however, slow deprotonation of this adduct enables aminopalladation to be reversible, and product formation proceeds through the thermodynamically preferred anti-Markovnikov aminopalladation adduct to yield 3.     

Mechanistic imperatives for aldose-ketose isomerization in water: specific, general base- and metal ion-catalyzed isomerization of glyceraldehyde with proton and hydride transfer.

The deuterium enrichment of dihydroxyacetone obtained from the aldose-ketose isomerization of D,L-glyceraldehyde in D(2)O at 25 degrees C was determined by (1)H NMR spectroscopy from the integrated areas of the signals for the alpha-CH(2) and alpha-CHD groups of the product. One mole equivalent of deuterium is incorporated into the product when the isomerization is carried out in 150 mM pyrophosphate buffer at pD 8.4, but only 0.6 mol equiv of deuterium is incorporated into the product of isomerization in the presence of 0.01 M deuterioxide ion, so that 40% of the latter isomerization reaction proceeds by the intramolecular transfer of hydride ion. Several pathways were identified for catalysis of the isomerization of glyceraldehyde to give dihydroxyacetone. The isomerization with hydride transfer is strongly catalyzed by added Zn(2+). Deprotonation of glyceraldehyde is rate-determining for isomerization with proton transfer, and this proton-transfer reaction is catalyzed by Br?nsted bases. Proton transfer also occurs by a termolecular pathway with catalysis by the combined action of Br?nsted bases and Zn(2+). These results show that there is no large advantage to the spontaneous isomerization of glyceraldehyde in alkaline solution with either proton or hydride transfer, and that effective catalytic pathways exist to stabilize the transition states for both of these reactions in water. The existence of separate enzymes that catalyze the isomerization of sugars with hydride transfer and the isomerization of sugar phosphates with proton transfer is proposed to be a consequence of the lack of any large advantage to reaction by either of these pathways for the corresponding nonenzymatic isomerization in water.     

Glycine enolates: the effect of formation of iminium ions to simple ketones on alpha-amino carbon acidity and a comparison with pyridoxal iminium ions

Equilibrium constants in D2O were determined by 1H NMR analyses for formation of imines/iminium ions from addition of glycine methyl ester to acetone and from addition of glycine to phenylglyoxylate. First-order rate constants, also determined by 1H NMR, are reported for deuterium exchange between solvent D2O and the alpha-amino carbon of glycine methyl ester and glycine in the presence of increasing concentrations of ketone and Br?nsted bases. These rate and equilibrium data were used to calculate second-order rate constants for deprotonation by DO- and by Br?nsted bases of the alpha-imino carbon of the ketone adducts. Formation of the iminium ion between acetone and glycine methyl ester and between phenylglyoxylate and glycine is estimated to cause 7 unit and 15 unit decreases, respectively, in the pKa's of 21 and 29 for deprotonation of the parent carbon acids. The effect of formation of iminium ions to phenylglyoxylate and to 5'-deoxypyridoxal (DPL) [Toth, K.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 3013-3021] on the carbon acidity of glycine is similar. However, DPL is a much better catalyst than phenylglyoxylate of deprotonation of glycine, because of the exceptionally large thermodynamic driving force for conversion of the amino acid and DPL to the reactive iminium ion.     

A Marcus treatment of rate constants for protonation of ring-substituted alpha-methoxystyrenes: intrinsic reaction barriers and the shape of the reaction coordinate

Rate and equilibrium constants were determined for protonation of ring-substituted -methoxystyrenes by hydronium ion and by carboxylic acids to form the corresponding ring-substituted alpha-methyl alpha-methoxybenzyl carbocations at 25 degrees C and I = 1.0 (KCl). The thermodynamic barrier to carbocation formation increases by 14.5 kcal/mol as the phenyl ring substituent(s) is changed from 4-MeO- to 3,5-di-NO2-, and as the carboxylic acid is changed from dichloroacetic to acetic acid. The Br?nsted coefficient alpha for protonation by carboxylic acids increases from 0.67 to 0.77 over this range of phenyl ring substituents, and the Br?nsted coefficient beta for proton transfer increases from 0.63 to 0.69 as the carboxylic acid is changed from dichloroacetic to acetic acid. The change in these Br?nsted coefficients with changing reaction driving force, (inverted theta)alpha/ (inverted theta) deltaG(av) degrees=(inverted theta)beta/(inverted theta)delta G(av) degrees= 1/8lambda = 0.011, is used to calculate a Marcus intrinsic reaction barrier of lambda= 11 kcal/mol which is close to the barrier of 13 kcal/mol for thermoneutral proton transfer between this series of acids and bases. The value of alpha= 0.66 for thermoneutral proton transfer is greater than alpha= 0.50 required by a reaction that follows the Marcus equation. This elevated value of beta may be due to an asymmetry in the reaction coordinate that arises from the difference in the intrinsic barriers for proton transfer at the oxygen acid reactant and resonance-stabilized carbon acid product.     

Effect of hydrogen bonds on pKa values: importance of networking

The pK(a) of an acyclic aliphatic heptaol ((HOCH(2)CH(2)CH(OH)CH(2))(3)COH) was measured in DMSO, and its gas-phase acidity is reported as well. This tertiary alcohol was found to be 10(21) times more acidic than tert-butyl alcohol in DMSO and an order of magnitude more acidic than acetic acid (i.e., pK(a) = 11.4 vs 12.3). This can be attributed to a 21.9 kcal mol(-1) stabilization of the charged oxygen center in the conjugate base by three hydrogen bonds and another 6.3 kcal mol(-1) stabilization resulting from an additional three hydrogen bonds between the uncharged primary and secondary hydroxyl groups. Charge delocalization by both the first and second solvation shells may be used to facilitate enzymatic reactions. Acidity constants of a series of polyols were also computed, and the combination of hydrogen-bonding and electron-withdrawing substituents was found to afford acids that are predicted to be extremely acidic in DMSO (i.e., pK(a) < 0). These hydrogen bond enhanced acids represent an attractive class of Br?nsted acid catalysts.     

New insight on the origin of the unusual acidity of Meldrum's acid from ab initio and combined QM/MM simulation study.

Ab initio molecular orbital and combined QM/MM Monte Carlo simulations have been carried out to investigate the origin of the unusually high acidity of Meldrum's acid. Traditionally, the high acidity of Meldrum's acid relative to that of methyl malonate has been attributed to an additive effect due to the presence of two E esters in the dilactone system. However, the present study reveals that there is significant nonadditive effect that also makes major contributions. This results from preferential stabilization of the enolate anion over that of Meldrum's acid due to anomeric stereoelectronic interactions. To investigate solvent effects on the acidity in aqueous solution, the relative acidities of Z and E conformers of methyl acetate have been determined in combined ab initio QM/MM simulations. There is significant solvent effect on the conformational equilibria for both the neutral ester and its enolate anion in water, leading to stabilization of the E stereoisomer. However, the computed solvent effect of 4.4 kcal/mol in favor of the E isomer of methyl acetate is largely offset by the favorable solvation of 3.4 kcal/mol for the E conformer of the enolate anion. This leads to an enhanced acidity of 3.4 kcal/mol for the (E)-methyl acetate in water over the Z conformer. In Meldrum's acid, it is the preferential stabilization of the enolate anion due to anomeric effects coupled with the intrinsically higher acidity of the E conformation of ester that is responsible for its high acidity.     

Hydrogen bonding and dissociation effects on the gas phase proton transfer reactions of ozone

Recently, the proton affinity (PA) of ozone was experimentally determined by Cacace and Speranza [Science (1994) 265: 208] using a bracketing technique that involved the proton transfer (PT) reactions: O₃H⁺+B⇒O₃+BH⁺; for different Br?nsted bases B. These authors showed that the simple collision model is not adequate to describe PT. We now present a theoretical model reflecting this bracketing procedure by explicitly introducing H-bonding complexing, dissociation and PT contributions, to discuss the kinetic model that assumes that PT occurs through one elementary step. The methods used include semiempirical density functional theory and ab initio Hartree-Fock methods. The procedure is gauged by using estimated PA of ozone obtained from deprotonation reactions including the Br?nsted bases BNH₃, H₂O, HOCl, SO₂, CH₃F and Kr. The PA-obtained range was from 145.3 to 160.3 kcal/mol, in fair agreement with the experimental value of 148.0±3 kcal/mol. The model seems to be fairly independent of the reference bases used to evaluate the PA. H-bonding effects appear to be a determining factor to explain collision efficiencies. Received: 5 August 1997 / Accepted: 25 September 1997     

Why does fluoride anion accelerate transmetalation between vinylsilane and palladium(II)-vinyl complex? Theoretical study

Transmetalation between palladium(II)-vinyl complex and vinylsilane was theoretically investigated with the DFT and MP2 to MP4 methods to clarify the reaction mechanism and the reasons why fluoride anion accelerates the Pd-catalyzed cross-coupling reaction between vinyl iodide and vinylsilane. This transmetalation occurs with a very large activation barrier (45.8 kcal/mol) and a very large endothermicity (25.6 kcal/mol) in the absence of fluoride anion, where the potential energy change resulting from the solvation effect is evident. This is consistent with the experimental fact that this cross-coupling reaction does not proceed well in the absence of fluoride anion. The effects of fluoride anion were investigated in three possible reaction courses. In the first course, fluorovinylsilicate anion is formed before the transmetalation, and it reacts with the palladium(II)-vinyl complex. In the second course, an iodo ligand is substituted for fluoride anion, and then the transmetalation occurs between the palladium(II)-fluoro-vinyl complex and vinylsilane. In the third course, fluoride anion attacks the Si center of vinylsilane in the transition state of the transmetalation between the palladium(II)-iodo-vinyl complex and vinylsilane. Our theoretical calculation suggests that fluorovinylsilicate anion is not formed in the case of trimethylvinylsilane. In the second and third cases, the transmetalation occurs with a moderate activation barrier (E(a)) and a considerably large exothermicity (E(exo)): E(a) = 25.3 kcal/mol and E(exo) = 5.7 kcal/mol in the second course, and E(a) = 12.7 kcal/mol and E(exo) = 24.8 kcal/mol in the third course, indicating that fluoride anion accelerates the transmetalation via the second and third reaction courses. The acceleration of transmetalation by fluoride anion is clearly interpreted in terms of the formation of a very strong Si-F bond and the stabilization of the transition state by the hypervalent Si center, which is induced by the fluoride anion. Our computational results show that hydroxide anion accelerates the transmetalation in a manner similar to that observed with fluoride anion. From these results, we predict that the electronegative anion accelerates this transmetalation because the electronegative group forms a strong covalent bond with the silyl group and facilitates the formation of the hypervalent Si center in the transition state.     

The aminolysis of N-aroyl beta-lactams occurs by a concerted mechanism

N-aroyl beta-lactams are imides with exo- and endocyclic acyl centres which react with amines in aqueous solution to give the ring opened beta-lactam aminolysis product. Unlike the strongly base catalysed aminolysis of beta-lactam antiobiotics, such as penicillins and cephaloridines, the rate law for the aminolysis of N-aroyl beta-lactams is dominated by a term with a first-order dependence on amine concentration in its free base form, indicative of an uncatalysed aminolysis reaction. The second-order rate constants for this uncatalysed aminolysis of N-p-methoxybenzoyl beta-lactam with a series of substituted amines generates a Br?nsted betanuc value of +0.90. This is indicative of a large development of positive effective charge on the amine nucleophile in the transition state. Similarly, the rate constants for the reaction of 2-cyanoethylamine with substituted N-aroyl beta-lactams gives a Br?nsted betalg value of -1.03 for different amide leaving groups and is indicative of considerable change in effective charge on the leaving group in the transition state. These observations are compatible with either a late transition state for the formation of the tetrahedral intermediate of a stepwise mechanism or a concerted mechanism with simultaneous bond formation and fission in which the amide leaving group is expelled as an anion. Amide anion expulsion is also indicated by an insignificant solvent kinetic isotope effect, kH2ORNH2/kD2ORNH2, of 1.01 for the aminolysis of N-benzoyl beta-lactam with 2-methoxyethylamine. The Br?nsted betalg value decreases from -1.03 to -0.71 as the amine nucleophile is changed from 2-cyanoethylamine to propylamine. The Br?nsted betanuc value is more invariant although it changes from +0.90 to +0.85 on changing the amide leaving group from p-methoxy to p-chloro substituted. The sensitivity of the Br?nsted betanuc and betalg values to the nucleofugality of the amide leaving group and the nucleophilicity of the amine nucleophiles, respectively, indicate coupled bond formation and bond fission processes.     

Substrate specificity for catalysis of phosphodiester cleavage by a dinuclear Zn(II) complex

The 2.4 kcal mol(-1) greater stabilization of the transition state for cleavage of the minimal substrate HpPNP compared to the nucleoside substrate UpPNP by the efficient dinuclear metal ion catalyst Zn2(L2O) provides evidence that access to the cationic core of Zn2(L2O) is sterically blocked for the bulkier nucleoside substrates, a flaw that will need to be dealt with in later generations of metal ion catalysts of RNA cleavage.     

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring-opened rapamycin-degradation product

Rapamycin (1), a macrolide immunosuppressant, undergoes degradation into ring-opened acid products 2 and 3 under physiologically relevant conditions. The unsaturated product (3) was isolated and studied in this work. Unlike 1, which has its amide primarily in a trans conformation in solution, 3 has both cis and trans conformations in approximately a 1:1 ratio in dimethyl sulfoxide (DMSO). The amount of cis rotamer was increased dramatically in the presence of an organic base such as triethylamine. The detailed NMR results indicate that the cis rotamer is stabilized through an intramolecular ionic hydrogen bond of the carboxylate anion with the tertiary alcohol as part of a nine-membered ring system. This hydrogen bond was characterized further in organic media and the trans-cis rotamer equilibria were used to estimate the relative bond strengths in several solvents. The additional stabilization arising from this ionic hydrogen bond in the cis rotamer was determined to be 1.4 kcal mol(-1) in DMSO-d6, 2.0 kcal mol(-1) in CD3CN and 1.1 kcal mol(-1) in CD3OD.     

OMP decarboxylase: phosphodianion binding energy is used to stabilize a vinyl carbanion intermediate

Orotidine 5'-monophosphate decarboxylase (OMPDC) catalyzes the exchange for deuterium from solvent D(2)O of the C-6 proton of 1-(β-d-erythrofuranosyl)-5-fluorouracil (FEU), a phosphodianion truncated product analog. The deuterium exchange reaction of FEU is accelerated 1.8 × 10(4)-fold by 1 M phosphite dianion (HPO(3)(2-)). This corresponds to a 5.8 kcal/mol stabilization of the vinyl carbanion-like transition state, which is similar to the 7.8 kcal/mol stabilization of the transition state for OMPDC-catalyzed decarboxylation of a truncated substrate analog by bound HPO(3)(2-). These results show that the intrinsic binding energy of phosphite dianion is used in the stabilization of the vinyl carbanion-like transition state common to the decarboxylation and deuterium exchange reactions.     

Energetics of direct and water-mediated proton-coupled electron transfer

Proton-coupled electron transfer (PCET) is an elementary chemical reaction crucial for biological oxidoreduction. We perform quantum chemical calculations to study the direct and water-mediated PCET between two stacked tyrosines, TyrO(?) + TyrOH → TyrOH + TyrO(?), to mimic a key step in the catalytic reaction of class Ia ribonucleotide reductase (RNR). The energy surfaces of electronic ground and excited states are separated by a large gap of ~20 kcal mol(-1), indicative of an electronically adiabatic transfer mechanism. In response to chemical substitutions of the proton donor, the energy of the transition state for direct PCET shifts by exactly half of the change in energetic driving force, resulting in a linear free energy relation with a Br?nsted slope of ?. In contrast, for water-mediated PCET, we observe integer Br?nsted slopes of 1 and 0 for proton acceptor and donor modifications, respectively. Our calculations suggest that the π-stacking of the tyrosine dimer in RNR results in strong electronic coupling and adiabatic PCET. Water participation in the PCET can be identified perturbatively in a Br?nsted analysis.