Gas-phase thermochemical properties of pyrimidine nucleobases

The gas-phase acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine have been examined using both theoretical (B3LYP/6-31+G*) and experimental (bracketing, Cooks kinetic) methods. This paper represents a comprehensive examination of multiple acidic sites of thymine and cytosine and of the acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine. Thymine exists as the most stable "canonical" tautomer in the gas phase, with a DeltaH(acid) of 335 +/- 4 kcal mol(-1) (DeltaG(acid) = 328 +/- 4 kcal mol(-1)) for the more acidic N1-H. The acidity of the less acidic N3-H site has not, heretofore, been measured; we bracket a DeltaH(acid) value of 346 +/- 3 kcal mol(-1) (DeltaG(acid) = 339 +/- 3 kcal mol(-1)). The proton affinity (PA = DeltaH) of thymine is measured to be 211 +/- 3 kcal mol(-1) (GB = DeltaG = 203 +/- 3 kcal mol(-1)). Cytosine is known to have several stable tautomers in the gas phase in contrast to in solution, where the canonical tautomer predominates. Using bracketing methods in an FTMS, we measure a DeltaH(acid) for the more acidic site of 342 +/- 3 kcal mol(-1) (DeltaG(acid) = 335 +/- 3 kcal mol(-1)). The DeltaH(acid) of the less acidic site, previously unknown, is 352 +/- 4 kcal mol(-1) (345 +/- 4 kcal mol(-1)). The proton affinity is 228 +/- 3 kcal mol(-1) (GB = 220 +/- 3 kcal mol(-1)). Comparison of these values to calculations indicates that we most likely have a mixture of the canonical tautomer and two enol tautomers and possibly an imine tautomer under our conditions in the gas phase. We also measure the acidity and proton affinity of cytosine using the extended Cooks kinetic method. We form the proton-bound dimers via electrospray of an aqueous solution, which favors cytosine in the canonical form. The acidity of cytosine using this method is DeltaH(acid) = 343 +/- 3 kcal mol(-1), PA = 227 +/- 3 kcal mol(-1). We also examined 1-methyl cytosine, which has fewer accessible tautomers than cytosine. We measure a DeltaH(acid) of 349 +/- 3 kcal mol(-1) (DeltaG(acid) = 342 +/- 3 kcal mol(-1)) and a PA of 230 +/- 3 kcal mol(-1) (GB = 223 +/- 3 kcal mol(-1)). Our ultimate goal is to understand the intrinsic reactivity of nucleobases; gas-phase acidic and basic properties are of interest for chemical reasons and also possibly for biological purposes because biological media can be quite nonpolar.     

Gas-phase acidity studies of multiple sites of adenine and adenine derivatives

The acidities of multiple sites in the purine nucleobase adenine (1) and adenine alkyl derivatives 9-ethyladenine (2), 3-methyladenine (3), 1-methyladenine (4), and N,N-dimethyladenine (5) have been investigated for the first time, using computational and experimental methods to provide an understanding of adenine reactivity. We have previously measured two acidic sites on adenine, with the N9 site being 19 kcal mol(-)(1) more acidic than the N10 site (333 +/- 2 versus 352 +/- 4 kcal mol(-)(1), respectively). In this work, we have established that 9-ethyladenine has two sites more acidic than water: the N10 (352 +/- 4 kcal mol(-)(1)) and the C8 (374 +/- 2 kcal mol(-)(1)). We have likewise measured two acidities for 3-methyladenine, the N10 (347 +/- 4 kcal mol(-)(1)) and the C2 (370 +/- 3 kcal mol(-)(1)). For 1-methyladenine and N,N-dimethyladenine, we measure the N9H acidity to be 331 +/- 2 and 333 +/- 2 kcal mol(-)(1), respectively. We believe that the bracketing of only one site for the latter species is a kinetic effect, which we discuss further in the paper. Computationally, we have found the interesting result that some of the vinylic C-H sites in these purine bases are predicted to be much more acidic than water (DeltaH(acid) = 390.7 kcal mol(-)(1)) in the gas phase, on the order of 373 kcal mol(-)(1). The acidic vinylic C-H sites are always adjacent to an N-R group, and this pattern is maintained regardless of whether the site is on the five- or six-membered ring of the purine. Vinylic C-H sites elsewhere on the purine have calculated acidities of about 400 kcal mol(-)(1). The differing acidities are interpreted through electrostatic potential calculations. We also relate our results to the intriguing biochemical decarboxylation of orotate ribose monophosphate, which involves a vinylic anion adjacent to an N-R group; this decarboxylation is the last step in the de novo biosynthesis of pyrimidine nucleotides, and the enzyme that catalyzes the reaction, orotate ribose monophosphate decarboxylase, has been the subject of intense study recently, as its mechanism remains elusive.     

Selectivity of purine alkylation by a quinone methide. Kinetic or thermodynamic control?

The alkylation reaction of 9-methyladenine and 9-methylguanine (as prototype substrates of deoxy-adenosine and -guanosine), by the parent o-quinone methide (o-QM), has been investigated in the gas phase and in aqueous solution, using density functional theory at the B3LYP/6-311+G(d,p) level. The effect of the medium on the reactivity, and on the stability of the resulting adducts, has been investigated by using the C-PCM solvation model to assess which adduct arises from the kinetically favorable path, or from an equilibrating process. The calculations indicate that the most nucleophilic site of the methyl-substituted nucleobases in the gas phase is the guanine oxygen atom (O(6)) (DeltaG()(gas) = 5.6 kcal mol(-)(1)), followed by the adenine N1 (DeltaG)(gas) = 10.3 kcal mol(-)(1)), while other centers exhibit a substantially lower nucleophilicity. The bulk effect of water as a solvent is the dramatic reduction of the nucleophilicity of both 9-methyladenine N1 (DeltaG)(solv) = 14.5 kcal mol(-)(1)) and 9-methylguanine O(6) (DeltaG)(solv) = 17.0 kcal mol(-)(1)). As a result there is a reversal of the nucleophilicity order of the purine bases. While O(6) and N7 nucleophilic centers of 9-methylguanine compete almost on the same footing, the reactivity gap between N1 and N7 of 9-methyladenine in solution is highly reduced. Regarding product stability, calculations predict that only two of the adducts of o-QM with 9-methyladenine, those at NH(2) and N1 positions, are lower in energy than reactants, both in the gas phase and in water. However, the adduct at N1 can easily dissociate in water. The adducts arising from the covalent modification of 9-methylguanine are largely more stable than reactants in the gas phase, but their stability is markedly reduced in water. In particular, the oxygen alkylation adduct becomes slightly unstable in water (DeltaG(solv) = +1.4 kcal mol(-)(1)), and the N7 alkylation product remains only moderately more stable than free reactants (DeltaG(solv) = -2.8 kcal mol(-)(1)). Our data show that site alkylations at the adenine N1 and the guanine O(6) and N7 in water are the result of kinetically controlled processes and that the selective modification of the exo-amino groups of guanine N2 and adenine N6 are generated by thermodynamic equilibrations. The ability of o-QM to form several metastable adducts with purine nucleobases (at guanine N7 and O(2), and adenine N1) in water suggests that the above adducts may act as o-QM carriers.     

Acidity of adenine and adenine derivatives and biological implications. A computational and experimental gas-phase study

The gas-phase acidities of adenine, 9-ethyladenine, and 3-methyladenine have been investigated for the first time, using computational and experimental methods to provide an understanding of the intrinsic reactivity of adenine. Adenine is found to have two acidic sites, with the N9 site being 19 kcal mol(-1) more acidic than the N10 site; the bracketed acidities are 333 +/- 2 and 352 +/- 4 kcal mol(-1), respectively. Because measurement of the less acidic site can be problematic, we benchmarked the adenine N10 measurement by bracketing the acidity of 9-ethyladenine, which has the N9 site blocked and allows for exclusive measurement of the N10 site. The acidity of 9-ethyladenine brackets to 352 +/- 4 kcal mol(-1), comparable to that of the N10 site of the parent adenine. Calculations and experiments with 3-methyladenine, a harmful mutagenic nucleobase, uncovered the surprising result that the most commonly written tautomer of 3-methyladenine is not the most stable in the gas phase. We have found that the most stable tautomer is the "N10 tautomer" 10, as opposed to the imine tautomer 3. The bracketed acidity of 10 is 347 +/- 4 kcal mol(-1). Since 10 is not a viable species in DNA, 3 is a likely tautomer; calculations indicate that this form has an extremely high acidity (320-323 kcal mol(-1)). The biological implications of these results, particularly with respect to enzymes that cleave alkylated bases from DNA, are discussed.     

Acidity and proton affinity of hypoxanthine in the gas phase versus in solution: intrinsic reactivity and biological implications

Hypoxanthine is a mutagenic purine base that most commonly arises from the oxidative deamination of adenine. Damaged bases such as hypoxanthine are associated with carcinogenesis and cell death. This inevitable damage is counteracted by glycosylase enzymes, which cleave damaged bases from DNA. Alkyladenine DNA glycosylase (AAG) is the enzyme responsible for excising hypoxanthine from DNA in humans. In an effort to understand the intrinsic properties of hypoxanthine, we examined the gas-phase acidity and proton affinity using quantum mechanical calculations and gas-phase mass spectrometric experimental methods. In this work, we establish that the most acidic site of hypoxanthine has a gas-phase acidity of 332 +/- 2 kcal mol-1, which is more acidic than hydrochloric acid. We also bracket a less acidic site of hypoxanthine at 368 +/- 3 kcal mol-1. We measure the proton affinity of the most basic site of hypoxanthine to be 222 +/- 3 kcal mol-1. DFT calculations of these values are consistent with the experimental data. We also use calculations to compare the acidic and basic properties of hypoxanthine with those of the normal bases adenine and guanine. We find that the N9-H of hypoxanthine is more acidic than that of adenine and guanine, pointing to a way that AAG could discriminate damaged bases from normal bases. We hypothesize that AAG may cleave certain damaged nucleobases as anions and that the active site may take advantage of a nonpolar environment to favor deprotonated hypoxanthine as a leaving group versus deprotonated adenine or guanine. We also show that an alternate mechanism involving preprotonation of hypoxanthine is energetically less attractive, because the proton affinity of hypoxanthine is less than that of adenine and guanine. Last, we compare the acidity in the gas phase versus that in solution and find that a nonpolar environment enhances the differences in acidity among hypoxanthine, adenine, and guanine.     

The acidity of uracil and uracil analogs in the gas phase: four surprisingly acidic sites and biological implications

The gas phase acidities of a series of uracil derivatives (1-methyluracil, 3-methyluracil, 6-methyluracil, 5,6-dimethyluracil, and 1,3-dimethyluracil) have been bracketed to provide an understanding of the intrinsic reactivity of uracil. The experiments indicate that in the gas phase, uracil has four sites more acidic than water. Among the uracil analogs, the N1-H sites have deltaH(acid) values of 331-333 kcal mol(-1); the acidity of the N3 sites fall between 347-352 kcal mol(-1). The vinylic C6 in 1-methyluracil and 3-methyluracil brackets to 363 kcal mol(-1), and 369 kcal mol(-1) in 1,3-dimethyluracil; the C5 of 1,3-dimethyluracil brackets to 384 kcal mol(-1). Calculations conducted at B3LYP/6-31+G* are in agreement with the experimental values. The bracketing of several of these sites involved utilization of an FTMS protocol to measure the less acidic site in a molecule that has more than one acidic site, establishing the generality of this method. In molecules with multiple acidic sites, only the two most acidic sites were bracketable, which is attributable to a kinetic effect. The measured acidities are in direct contrast to in solution, where the two most acidic sites of uracil (N1 and N3) are indifferentiable. The vinylic C6 site is also particularly acidic, compared to acrolein and pyridine. The biological implications of these results, particularly with respect to enzymes for which uracil is a substrate, are discussed.     

Interaction of adenine adducts with thymine: a computational study

The existence of DNA adducts bring the danger of carcinogenesis because of mispairing with normal DNA bases. 1,N6-ethenoadenine adducts (epsilonA) and 1,N6-ethanoadenine adducts (EA) have been considered as DNA adducts to study the interaction with thymine, as DNA base. Several different stable conformers for each type of adenine adduct with thymine, [epsilonA(1)-T(I), epsilonA(2)-T(I), epsilonA(3)-T(I) and EA(1)-T(I), EA(2)-T(I), EA(3)-T(I)] and [epsilonA(1)-T(II), epsilonA(2)-T(II), epsilonA(3)-T(II) and EA(1)-T(II), EA(2)-T(II), EA(3)-T(II)], have been considered with regard to their interactions. The differences in their geometrical structures, energetic properties, and hydrogen-bonding strengths have also been compared with Watson-Crick adenine-thymine base pair (A-T). Single-point energy calculations at MP2/6-311++G** levels on B3LYP/6-31+G* optimized geometries have also been carried out to better estimate the hydrogen-bonding strengths. The basis set superposition error corrected hydrogen-bonding strength sequence at MP2/6-311++G**//B3LYP/6-31+G* for the most stable complexes is found to be EA(2)-T(I) (15.30 kcal/mol) > EA(1)-T(II) (14.98 kcal/mol) > EA(3)-T(II) (14.68 kcal/mol) > epsilonA(2)-T(I) (14.54 kcal/mol) > epsilonA(3)-T(II) (14.22 kcal/mol) > epsilonA(3)-T(II) (13.64 kcal/mol) > A-T (13.62 kcal/mol). The calculated reaction enthalpy value for epsilonA(2)-T(I) is 10.05 kcal/mol, which is the highest among the etheno adduct-thymine complexes and about 1.55 kcal/mol more than those obtained for Watson-Crick A-T base pair and the reaction enthalpy value for EA(1)- T(II) is 10.22 kcal/mol, which is highest among the ethano addcut-thymine complexes and about 1.72 kcal/mol more than those obtained for Watson-Crick A-T base pair. The aim of this research is to provide fundamental understanding of adenine adduct and thymine interaction at the molecular level and to aid in future experimental studies toward finding the possible cause of DNA damage.     

Experimental determination of the alpha and beta C--H bond dissociation energies in naphthalene

The acidities of the two different sites in naphthalene (1alpha and 1beta) and the electron affinities of the alpha- and beta-naphthyl radicals were measured using a Fourier transform mass spectrometer. Both carbon-hydrogen bond dissociation energies for naphthalene also were obtained, in this case via the application of a thermodynamic cycle. The final results are DeltaH(o)acid (1alpha) = 394.2+/-1.2 kcal mol(-1), DeltaH(o)acid (1beta) = 395.5+/-1.3 kcal mol(-1), EA(alpha) = 31.6+/-0.5 kcal mol(-1), EA(beta) = 31.6+/-0.5 kcal mol(-1), BDE(1alpha) = 112.2+/-1.3 kcal mol(-1) and BDE(1alpha) = 111.9+/-1.4 kcal mol(-1), and they are compared to benzene and phenyl radical as well as ab initio and density functional theory (B3LYP) calculations.     

Theoretical study of cisplatin binding to purine bases: why does cisplatin prefer guanine over adenine?

The thermodynamics and kinetics for the monofunctional binding of the antitumor drug cisplatin, cis-diamminedichloroplatinum(II), to a purine base site of DNA were studied computationally using guanine and adenine as model reactants. A dominating preference for initial attack at the N7-position of guanine is established experimentally, which is a crucial first step for the formation of a 1,2-intrastrand cross-link of adjacent guanine bases that leads to bending and unwinding of DNA. These structural distortions are proposed ultimately to be responsible for the anticancer activity of cisplatin. Utilizing density functional theory in combination with a continuum solvation model, we developed a concept for the initial Pt-N7 bond formation to atomic detail. In good agreement with experiments that suggested DeltaG++ = approximately 23 kcal/mol for the monofunctional platination of guanine, our model gives DeltaG++ = 24.6 kcal/mol for guanine, whereas 30.2 kcal/mol is computed when adenine is used. This result predicts that guanine is 3-4 orders of magnitude more reactive toward cisplatin than adenine. A detailed energy decomposition and molecular orbital analysis was conducted to explain the different barrier heights. Two effects are equally important to give the preference for guanine over adenine: First, the transition state is characterized by a strong hydrogen bond between the ammine-hydrogen of cisplatin and the O=C6 moiety of guanine in addition to a stronger electrostatic interaction between the two reacting fragments. When adenine binds, only a weak hydrogen bond forms between the chloride ligand of cisplatin and the H(2)N-C6 group of adenine. Second, a significantly stronger molecular orbital interaction is identified for guanine compared to adenine. A detailed MO analysis is presented to provide an intuitive view into the different electronic features governing the character of the Pt-N7 bond in platinated purine bases.     

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.     

Theoretical study of the adsorption of DNA bases on the acidic external surface of montmorillonite

In the present study, DFT periodic plane wave calculations, at the PBE-D level of theory, were carried out to investigate the interaction of DNA nucleobases with acidic montmorillonite. The surface model was considered in its octahedral (Osub) and tetrahedral (Tsub) substituted forms, known to have different acidic properties. The adsorption of adenine, guanine and cytosine was considered in both orthogonal and coplanar orientations with the surface, interacting with the proton via a given heteroatom. In almost all considered cases, adsorption involved the spontaneous proton transfer to the nucleobase, with a more pronounced character in the Osub structures. The binding energy is about 10 kcal mol(-1) larger for Osub than for Tsub complexes mainly due to the larger acidity in Osub surfaces and due to the better stabilization by H-bond contacts between the negatively charged surface and the protonated base. The binding energy of coplanar orientations of the base is observed to be as large as the orthogonal ones due to a balance between electrostatic and dispersion contributions. Finally the binding of guanine and adenine on the acidic surface amounts to 50 kcal mol(-1) while that of cytosine rises to 44 kcal mol(-1).     

Modeling the chemical step utilized by human alkyladenine DNA glycosylase: a concerted mechanism AIDS in selectively excising damaged purines

Human alkyladenine DNA glycosylase (AAG) initiates the repair of a wide variety of (neutral or cationic) alkylated and deaminated purines by flipping damaged nucleotides out of the DNA helix and catalyzing the hydrolytic N-glycosidic bond cleavage. Unfortunately, the limited number of studies on the catalytic pathway has left many unanswered questions about the hydrolysis mechanism. Therefore, detailed ONIOM(M06-2X/6-31G(d):AMBER) reaction potential energy surface scans are used to gain the first atomistic perspective of the repair pathway used by AAG. The lowest barrier for neutral 1,N(6)-ethenoadenine (εA) and cationic N(3)-methyladenine (3MeA) excision corresponds to a concerted (A(N)D(N)) mechanism, where our calculated ΔG(?) = 87.3 kJ mol(-1) for εA cleavage is consistent with recent kinetic data. The use of a concerted mechanism supports previous speculations that AAG uses a nonspecific strategy to excise both neutral (εA) and cationic (3MeA) lesions. We find that AAG uses nonspecific active site DNA-protein π-π interactions to catalyze the removal of inherently more difficult to excise neutral lesions, and strongly bind to cationic lesions, which comes at the expense of raising the excision barrier for cationic substrates. Although proton transfer from the recently proposed general acid (protein-bound water) to neutral substrates does not occur, hydrogen-bond donation lowers the catalytic barrier, which clarifies the role of a general acid in the excision of neutral lesions. Finally, our work shows that the natural base adenine (A) is further inserted into the AAG active site than the damaged substrates, which results in the loss of a hydrogen bond with Y127 and misaligns the general base (E125) and water nucleophile to lead to poor nucleophile activation. Therefore, our work proposes how AAG discriminates against the natural purines in the chemical step and may also explain why some damaged pyrimidines are bound but are not excised by this enzyme.     

Dynamical intramolecular metal-to-metal ligand exchange of phosphine and thioether ligands in derivatives PtRu5(CO)16(mu6-C)

The complexes PtRu(5)(CO)(15)(PMe(2)Ph)(mu(6)-C) (2), PtRu(5)(CO)(14)(PMe(2)Ph)(2)(mu(6)-C) (3), PtRu(5)(CO)(15)(PMe(3))(mu(6)-C) (4), PtRu(5)(CO)(14)(PMe(3))(2)(mu(6)-C) (5), and PtRu(5)(CO)(15)(Me(2)S)(mu(6)-C) (6) were obtained from the reactions of PtRu(5)(CO)(16)(mu(6)-C) (1) with the appropriate ligand. As determined by NMR spectroscopy, all the new complexes exist in solution as a mixture of isomers. Compounds 2, 3, and 6 were characterized crystallographically. In all three compounds, the six metal atoms are arranged in an octahedral geometry, with a carbido carbon atom in the center. The PMe(2)Ph and Me(2)S ligands are coordinated to the Pt atom in 2 and 6, respectively. In 3, the two PMe(2)Ph ligands are coordinated to Ru atoms. In solution, all the new compounds undergo dynamical intramolecular isomerization by shifting the PMe(2)Ph or Me(2)S ligand back and forth between the Pt and Ru atoms. For compound 2, DeltaH++ = 15.1(3) kcal/mol, DeltaS++ = -7.7(9) cal/(mol.K), and DeltaG(298) = 17.4(6) kcal/mol for the transformation of the major isomer to the minor isomer; for compound 4, DeltaH++ = 14.0(1) kcal/mol, DeltaS++ = -10.7(4) cal/(mol.K), and DeltaG(298) = 17.2(2) kcal/mol for the transformation of the major isomer to the minor isomer; for compound 6, DeltaH++ = 18(1) kcal/mol, DeltaS++ = 21(5) cal/(mol.K) and DeltaG(298) = 12(2) kcal/mol. The shifts of the Me(2)S ligand in 6 are significantly more facile than the shifts for the phosphine ligand in compounds 2-5. This is attributed to a more stable ligand-bridged intermediate for the isomerizations of 6 than that for compounds 2-5. The intermediate for the isomerization of 6 involves a bridging Me(2)S ligand that can use two lone pairs of electrons for coordination to the metal atoms, whereas a tertiary phosphine ligand can use only one lone pair of electrons for bridging coordination.     

The boron-catalyzed polymerization of dimethylsulfoxonium methylide. A living polymethylene synthesis

Trialkyl and aryl organoboranes catalyze the polymerization of dimethylsulfoxonium methylide (1). The product of the polymerization is a tris-polymethylene organoborane. Oxidation affords linear telechelic alpha-hydroxy polymethylene. The polymer molecular weight was found to be directly proportional to the stoichiometric ratio of ylide/borane, and polydispersities as low as 1.01-1.03 have been realized. Although oligomeric polymethylene has been the most frequent synthetic target of this method, polymeric star organoboranes with molecular weights of 1.5 million have been produced. The average turnover frequency at 120 degrees C in 1,2,4,5-tetrachlorobenzene/toluene is estimated at >6 x 10(6) g of polymethylene (mol boron)(-1) h(-1). The mechanism of the polyhomologation reaction involves initial formation of a zwitterionic organoborane.ylide complex which breaks down in a rate-limiting 1,2-alkyl group migration with concomitant expulsion of a molecule of DMSO. The reaction was found to be first order in the borane catalyst and zero order in ylide. DMSO does not interfere with the reaction. The temperature dependence of the reaction rate yielded the following activation energy parameters (toluene, DeltaH(++) = 23.2 kcal/mol, DeltaS(++) = 12.6 cal deg/mol, DeltaG(++) = 19.5 kcal/mol; THF, DeltaH(++) = 26.5 kcal/mol, DeltaS(++) = 21.5 cal deg/mol, DeltaG(++) = 20.1 kcal/mol).     

An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines

The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithium in the presence of sparteine-like diamines has been studied experimentally and computationally at various theoretical levels through to B3P86/6-31G*. Of the (-)-cytisine-derived diamines (N-Me, N-Et, N-(n)Bu, N-CH(2)(t)Bu, N-(i)Pr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the least sterically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., opposite enantioselectivity to (-)-sparteine. The experimental result with the N-Me-substituted diamine correlated well with the computational results: at the B3P86/6-31G* level, the sense of induction was correctly predicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowest activation energy (DeltaH++ = 11.1 kcal/mol, DeltaG++= 11.5 kcal/mol) for proton transfer. The computational results with the N-(i)Pr-substituted diamine identified a transition state for proton transfer with activation energies of DeltaH++= 11.7 kcal/mol and DeltaG++= 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to (-)-sparteine and the N-Me-substituted diamine, these DeltaH++ and DeltaG++ values are at odds with the experimental observation that use of the N-(i)Pr-substituted diamine gave no product. It is suggested that steric crowding inhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transfer in the transition state. Three other ligands (N-H and O-substituted as well as a five-membered ring analogue) were studied solely using computational methods, and the results predict that the observed enantioselectivity would be modest at best.     

Peculiar structure of the HOOO(-) anion

The HOOO(-) anion (1) can adopt a triplet state (T-1) or a singlet state (S-1), where the former is 9.8 kcal/mol (DeltaH(298) = 10.3 kcal/mol) more stable than the latter. S-1 possesses a strong O-OOH bond with some double bond character and a weakly covalent OO-OH bond (1.80 A) according to CCSD(T)/6-311++G(3df,3pd) calculations (the longest O-O bond ever found for a peroxide). In aqueous solution, S-1 adopts a geometry closely related to that of HOOOH (OO(O), 1.388 A; (O)OO(H), 1.509 A; tau(OOOH), 78.3 degrees ), justifying that S-1 is considered the anion of HOOOH. Dissociation into HO anion and O(2)((1)Delta(g)) requires 15.4 (DeltaH(298) = 14.3; DeltaG(298) = 8.9) kcal/mol. Structure T-1 corresponds to a van der Waals complex between HO anion and O(2)((3)Sigma(g)(-)) having a binding energy of 2.7 (DeltaH(298) = 2.1) kcal/mol. Modes of generating S-1 in aqueous solution are discussed, and it is shown that S-1 represents an important intermediate in ozonation reactions.     

Gas-phase acidities of disubstituted methanes and of enols of carboxamides substituted by electron-withdrawing groups

The gas-phase acidities DeltaG degrees (acid) of some 20 amides/enols of amides RNHCOCHYY'/RNHC(OH)=CYY' [R = Ph, i-Pr; Y, Y' = CO(2)R', CO(2)R' ', or CN, CO(2)R', R', R' ' = Me, CH(2)CF(3), CH(CF(3))(2)], the N-Ph and N-Pr-i amides of Meldrum's acid, 1,3-cyclopentanedione, dimedone, and 1,3-indanedione, and some N-p-BrC(6)H(4) derivatives and of nine CH(2)YY' (Y, Y' = CN, CO(2)R', CO(2)R' '), including the cyclic carbon acids listed above, were determined by ICR. The acidities were calculated at the B3LYP/6-31+G//B3LYP/6-31+G level for both the enol and the amide species or for the carbon acid and the enol on the CO in the CH(2)YY' series. For 12 of the compounds, calculations were also conducted with the larger base sets 6-311+G and G-311+G. The DeltaG degrees (acid) values changed from 341.3 kcal/mol for CH(2)(CO(2)Me)(2) to 301.0 kcal/mol for PhNHC(OH)=C(CN)CH(CF(3))(2). The acidities increased for combinations of Y and Y' based on the order CO(2)Me < CO(2)CH(2)CF(3) < CN, CO(2)CH(CF(3))(2) for a single group and reflect the increased electron-withdrawal ability of Y,Y' coupled with the ability to achieve planarity of the crowded anion. The acidities of corresponding YY'-substituted systems follow the order N-Ph enols > N-Pr-i enols > CH(2)YY'. Better linear relationships between DeltaG degrees (acid) values calculated for the enols and the observed values than those for the values calculated for the amides suggest that the ionization site is the enolic O-H of most of the noncyclic trisubstituted methanes. The experimental DeltaG degrees (acid) value for Meldrum's acid matches the recently reported calculated value. The calculated structures and natural charges of all species are given, and the changes occurring in them on ionization are discussed. Correlations between the DeltaG degrees (acid) values and the pK(enol) values, which are linear for the trisubstituted methanes, excluding YY' = (CN)(2) and nonlinear for the CH(2)YY' systems, are discussed.     

Theoretical study on the gas-phase acidity of multiple sites of Cu+-adenine and Cu2+-adenine complexes

The acidities of multiple sites in Cu(+)-adenine and Cu(2+)-adenine complexes have been investigated theoretically. To compare, the acidities of adenine (A) and adenine radical cation (A(*+)) have also been included. The results clearly indicate that the acidities of C-H and N-H groups in Cu(+/2+)-adenine are significantly enhanced relative to the neutral adenine. The acidic order for a given site on adenine and adenine derivatives is as follows: Cu(2+)-adenine > A(*+) > Cu(+)-adenine > A. For Cu(+)-adenine and Cu(2+)-adenine, N3-coordination exhibits N9-H acid, and N1- and N7-coordination exhibits N6-H(a) and N6-H(b) acid, respectively. Additionally, it is found that C2-H group is surprisingly acidic in the coordination complexes. Calculations in aqueous solution reveal that our results can be extrapolated to aqueous solution. Analyses of the electronic properties interpret the highest acidity of Cu(2+)-adenine among the adenine derivatives studied. Also, Electrostatic potential calculations of [A(-H(+))](-) and [A(-H(+))](*) indicate that the removal of H(a) or H(b) from the amino group favors the bidentate coordination, which provides a dative bond from the deprotonated N and the original coordination ligand to copper ion besides the electrostatic interaction between them and thereby stabilizes the [A(-H(+))](-)/[A(-H(+))](*). NBO analysis confirms the electrostatic potential result.     

Temperature effects on the catalytic activity of the D38E mutant of 3-oxo-Delta5-steroid isomerase: favorable enthalpies and entropies of activation relative to the nonenzymatic reaction catalyzed by acetate ion

3-oxo-Delta5-steroid isomerase (ketosteroid isomerase, KSI) catalyzes the isomerization of 5-androstene-3,17-dione (1) to 4-androstene-3,17-dione (3) via a dienolate intermediate (2-). KSI catalyzes this conversion about 13 orders of magnitude faster than the corresponding reaction catalyzed by acetate ion, a difference in activation energy (DeltaG) of approximately 18 kcal/mol. To evaluate whether the decrease in DeltaG by KSI is due to enthalpic or entropic effects, the activation parameters for the isomerization of 1 catalyzed by the D38E mutant of KSI were determined. A linear Arrhenius plot of kcat/KM versus 1/T gives the activation enthalpy (DeltaH = 5.9 kcal/mol) and activation entropy (TDeltaS = -2.6 kcal/mol). Relative to catalysis by acetate, D38E reduces DeltaH by approximately 10 kcal/mol and increases TDeltaS by approximately 5 kcal/mol. The activation parameters for the microscopic rate constants for D38E catalysis were also determined and compared to those for the acetate ion-catalyzed reaction. Enthalpic stabilization of 2- and favorable entropic effects in both chemical transition states by D38E result in an overall energetically more favorable enzymatic reaction relative to that catalyzed by acetate ion.     

Structure and conformations of N-(fluoroformyl)imidosulfurous dichloride,FC(O)N=SCl2

The IR (gas) and Raman (liquid) spectra of FC(O)NSCl(2) demonstrate the presence of a conformational mixture in both phases. According to a gas electron diffraction study, the main conformer (94(8)%) possesses a syn-syn structure (C(O)F group synperiplanar with respect to the SCl(2) bisector and the C=O bond synperiplanar to the N=S bond). Quantum chemical calculations (HF, B3LYP and MP2 with 6-31G basis set, and MP2/6-311(2df)) predict a syn-anti structure for the second conformer. Analysis of the IR (gas) spectrum results in a contribution of 5(1)% of the minor form, corresponding to a Gibbs free energy difference DeltaG degrees = G degrees (syn-anti) - G degrees (syn-syn) = 1.75(15) kcal/mol. This value is reproduced very well by quantum chemical calculations, which include electron correlation effects (DeltaG degrees = 1.28-1.56 kcal/mol). The HF approximation overestimates this energy difference (DeltaG degrees = 3.24 kcal/mol).