Deprotonation Enthalpies Research Articles

Thermodynamics of Zn2+Binding to Cys2His2and Cys2HisCys Zinc Fingers and a Cys4Transcription Factor Site

The thermodynamics of Zn(2+) binding to three peptides corresponding to naturally occurring Zn-binding sequences in transcription factors have been quantified with isothermal titration calorimetry (ITC). These peptides, the third zinc finger of Sp1 (Sp1-3), the second zinc finger of myelin transcription factor 1 (MyT1-2), and the second Zn-binding sequence of the DNA-binding domain of glucocorticoid receptor (GR-2), bind Zn(2+) with Cys(2)His(2), Cys(2)HisCys, and Cys(4) coordination, respectively. Circular dichroism confirms that Sp1-3 and MyT1-2 have considerable and negligible Zn-stabilized secondary structure, respectively, and indicate only a small amount for GR-2. The pK(a)'s of the Sp1-3 cysteines and histidines were determined by NMR and used to estimate the number of protons displaced by Zn(2+) at pH 7.4. ITC was also used to determine this number, and the two methods agree. Subtraction of buffer contributions to the calorimetric data reveals that all three peptides have a similar affinity for Zn(2+), which has equal enthalpy and entropy components for Sp1-3 but is more enthalpically disfavored and entropically favored with increasing Cys ligands. The resulting enthalpy-entropy compensation originates from the Zn-Cys coordination, as subtraction of the cysteine deprotonation enthalpy results in a similar Zn(2+)-binding enthalpy for all three peptides, and the binding entropy tracks with the number of displaced protons. Metal and protein components of the binding enthalpy and entropy have been estimated. While dominated by Zn(2+) coordination to the cysteines and histidines, other residues in the sequence affect the protein contributions that modulate the stability of these motifs.

Carbonic anhydrase inhibitors: A quantum mechanical study of interaction between some antiepileptic drugs with active center of carbonic anhydrase enzyme

Density functional theory (DFT) using B3LYP and split-valance 6-31G* basis set have been employed to calculate the details of electronic structure and electronic energy of carbonic anhydrase enzyme active center (CA), six inhibitors of this enzyme including topiramate and its derivatives and its analogue, and complex between these inhibitors and active center of carbonic anhydrase. Also thermodynamic functions such as deprotonation enthalpy of inhibitors, standard enthalpies of formation (ΔHf∘), standard entropy of formation (ΔSf∘) and standard Gibbs free energy of formation (ΔGf∘) for six CA–inhibitor complexes are evaluated. The calculated results indicate that deprotonated inhibitors are coordinated to the Zn2+ ion and all the complexes have tetrahedral geometry. According to the calculated thermodynamic functions substitution of sulfonamide group with hydroxyl reduces the tendency of inhibitor to bind to the active center of carbonic anhydrase. In all calculations solvent effects have been considered in water using SCRF method.

C–H Bond Strengths and Acidities in Aromatic Systems: Effects of Nitrogen Incorporation in Mono-, Di-, and Triazines

The negative ion chemistry of five azine molecules has been investigated using the combined experimental techniques of negative ion photoelectron spectroscopy to obtain electron affinities (EA) and tandem flowing afterglow-selected ion tube (FA-SIFT) mass spectrometry to obtain deprotonation enthalpies (Δ(acid)H(298)). The measured Δ(acid)H(298) for the most acidic site of each azine species is combined with the EA of the corresponding radical in a thermochemical cycle to determine the corresponding C-H bond dissociation energy (BDE). The site-specific C-H BDE values of pyridine, 1,2-diazine, 1,3-diazine, 1,4-diazine, and 1,3,5-triazine are 110.4 ± 2.0, 111.3 ± 0.7, 113.4 ± 0.7, 107.5 ± 0.4, and 107.8 ± 0.7 kcal mol(-1), respectively. The application of complementary experimental methods, along with quantum chemical calculations, to a series of nitrogen-substituted azines sheds light on the influence of nitrogen atom substitution on the strength of C-H bonds in six-membered rings.

Photoelectron Spectroscopy of Anilinide and Acidity of Aniline

The photoelectron spectrum of the anilinide ion has been measured. The spectrum exhibits a vibrational progression of the CCC in-plane bending mode of the anilino radical in its electronic ground state. The observed fundamental frequency is 524 ± 10 cm(-1). The electron affinity (EA) of the radical is determined to be 1.607 ± 0.004 eV. The EA value is combined with the N-H bond dissociation energy of aniline in a negative ion thermochemical cycle to derive the deprotonation enthalpy of aniline at 0 K; Δ(acid)H(0)(PhHN-H) = 1535.4 ± 0.7 kJ mol(-1). Temperature corrections are made to obtain the corresponding value at 298 K and the gas-phase acidity; Δ(acid)H(298)(PhHN-H) = 1540.8 ± 1.0 kJ mol(-1) and Δ(acid)G(298)(PhHN-H) = 1509.2 ± 1.5 kJ mol(-1), respectively. The compatibility of this value in the acidity scale that is currently available is examined by utilizing the acidity of acetaldehyde as a reference.

Fundamental Thermochemical Properties of Amino Acids: Gas-Phase and Aqueous Acidities and Gas-Phase Heats of Formation

The gas-phase acidities of the 20 L-amino acids have been predicted at the composite G3(MP2) level. A broad range of structures of the neutral and anion were studied to determine the lowest energy conformer. Excellent agreement is found with the available experimental gas-phase deprotonation enthalpies, and the calculated values are within experimental error. We predict that tyrosine is deprotonated at the CO(2)H site. Cysteine is predicted to be deprotonated at the SH but the proton on the CO(2)H is shared with the S(-) site. Self-consistent reaction field (SCRF) calculations with the COSMO parametrization were used to predict the pK(a)'s of the non-zwitterion form in aqueous solution. The differences in the non-zwitterion pK(a) values were used to estimate the free energy difference between the zwitterion and nonzwitterion forms in solution. The heats of formation of the neutral compounds were calculated from atomization energies and isodesmic reactions to provide the first reliable set of these values in the gas phase. Further calculations were performed on five rare amino acids to predict their heats of formation, acidities, and pK(a) values.

A theoretical investigation of the interaction between substituted carbonyl derivatives and water: Open or cyclic complexes?

The structures and binding energies of complexes between substituted carbonyl bases and water are the B3LYP/6-311++G(d,p) computational level. The calculations also include the proton affinity (PA) of the O of the C=O group, the deprotonation enthalpies (DPE) of the CH bonds along a natural bond orbital analysis. The calculations reveal that stable open C=O···H(w) O(w) as well as cyclic CH···O(w)H(w) ···O=C complexes are formed. The binding energies for the open complexes are linearly related to the PAs, whereas the binding energies for the cyclic complexes depend on both the PA and DPE. Different indicators of hydrogen bonds strength such as electron charge density, intramolecular and intermolecular hyperconjugation energy, occupation of orbitals, and charge transfer show significant differences between open and cyclic complexes. The contraction of the CH bond of the formyl group and the corresponding blue shift of the ν(CH) vibration are explained by the classical trans lone pair effect. In contrast, the elongation or contraction of the CH(3) group involved in the interaction with water results from the variation of the orbital interaction energies from the σ(CH) bonding orbital to the σ* and π* antibonding orbitals of the C=O group. The resulting blue or red shifts of the ν(CH(3)) vibrations are calculated in the partially deuterated isotopomers.

Gas phase acidity of a cysteine residue in small oligopeptides

The conformational effects on the gas-phase acidities of small cysteine-containing peptides were examined using ten oligopeptides. The gas-phase deprotonation enthalpies were measured using the extended Cooks kinetic method with full entropy analysis. The experiments were carried out using a triple quadrupole mass spectrometer. The values of ΔacidH were determined to be 335.6±1.7kcal/mol (AlaCysNH2), 334.6±1.8kcal/mol (Ala2CysNH2), 331.2±1.8kcal/mol (CysAlaNH2), 330.5±2.0kcal/mol (CysAla2NH2), 329.7±1.8kcal/mol (AlaCysAlaNH2), 335.3±1.8kcal/mol (GlyCysNH2), 334.6±1.7kcal/mol (Gly2CysNH2), 330.4±1.8kcal/mol (CysGlyNH2), 329.7±1.8kcal/mol (CysGly2NH2), and 327.3±2.0kcal/mol (GlyCysGlyNH2). The gas-phase acidities (ΔacidG) and the deprotonation entropies (ΔacidS) for these peptides were determined accordingly. These results suggested that the tripeptides were more acidic than the corresponding dipeptides by about 1kcal/mol, and the N-cysteine peptides were more acidity than the isomeric C-cysteine peptides by about 4kcal/mol. The initial conformations of the peptides were modeled via a conformational search using the MMFF method. The final geometries and energies were calculated at the B3LYP/6-31++G(d,p) level of theory. The calculated enthalpies of deprotonation agreed reasonably well with the experimental results. The conformations of the deprotonated N-cysteine peptides were more compact than those of the C-cysteine analogues. The more compact conformations allowed more efficient multiple hydrogen-bonding interactions between the thiolate anion and the nearby NH bonds. The greater acidities of the N-cysteine peptides were likely the results of the more favorable hydrogen-bonding and charge–amide dipole interactions that stabilized the thiolate anions more efficiently.

Hydrogen bond cooperativity in dimers of hydroxamic acids

AbstractMolecular orbital calculations are performed on various dimeric forms of four tautomers each of thioformohydroxamic acid and formohydroxamic acid. The analysis of stabilization energies associated with the dimerization and their correlation to proton affinities and deprotonation enthalpies of different potential sites present in the molecules indicate that the highest stabilization results when the most basic, site of the molecule acts as hydrogen bond acceptor but combination of the most acidic and the most basic site does not result in the largest stabilization when dimerization occurs. The presence of hydrogen bond cooperativity is indicated and the reasons for the observed cooperativity are explored in this study. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

Theoretical calculation of heats of formation, bond dissociation energies, and gas-phase acidities of fluoromethanes, chloromethanes, and eight other monoderivatives of methane

The heats of formation (HOFs), bond dissociation energies (BDEs) and gas-phase acidities (GPAs) of small methane halogenated (F, Cl) and monoderivatives of methane molecules were theoretically calculated, and the results were compared with the available experimental values in order to examine the accuracy of the six high levels of ab initio calculations CBS-Q, CBS-QB3, G2, G3, G3B3 and G4 in thermochemical studies. The HOFs were derived from ab initio calculations and thermodynamic cycles, using experimentally measured reactions and formation enthalpies. The HOFs of all the radicals of CH 3, CH 2X and X (X = F, Cl, C, O, N) were calculated by atomization reactions. The bond dissociation energies of homolytic cleavage of C–H and C–X (X = F, Cl, C, O, N) bond at 298.15 K were calculated. The gas-phase acidities were measured for the H-contained molecules, and the values were combined with the previously reported gas-phase deprotonation enthalpies. Regarding the calculated HOFs, BDEs and GPAs of the set of molecules, G4 theory was found to be the most accurate, with an RMS deviation of 1.62, 5.39, 3.61 kJ mol −1 respectively.

Thermochemistry of TM(II) Complexes (TM=Ni, Cu and Zn) and Their Ligands from DFT Calculations

Complexes of three transition-metal (TM) cations, Ni(II), Cu(II) and Zn(II), with four different ligands, namely, the tetradentate bis(acetylacetone)ethylenediamine, H2acacen, and bis(salicylidene)ethylenediimine, H2salen, ligands and the bidentate glycine, Hgly, and 8-hydroxyquinoline, Hox, ligands have been studied by means of the density functional theory based B3LYP method and considering all-electron basis sets. The enthalpies of deprotonation and of bond dissociation, at T=298.15 K, of the ligands were calculated and the values are found to be in very good agreement with available experimental data. The calculations were further extended to the standard molar enthalpies of formation in the gas-phase, T = 298.15 K, for the metal complexes by using pertinent working reactions and previously determined experimental enthalpies of formation for key species. Very good agreement was obtained and new values are estimated for the TM(gly)2 and Zn(acacen) complexes. In the cases of the Ni(gly)2 and Cu(gly)2 compounds, new values are suggested. Keywords: Density functional theory, Enthalpy of formation, Enthalpy of bond dissociation, Thermochemistry, Metal complex, Schiff base, Gas-phase acidity, Amino acid, Thermochemistry of TM(II) Complexes, DFT Calculations, transition-metal (TM), bidentate glycine, light-emitting materials, transition metals, Metal complexes, antibacterial, antimalarial, antineoplasic properties, hydroformilation, epoxidation, enthalpies of sublimation, reaction-solution calorimeter, isotenoscopic method, sublimation bulb technique, mass-loss Knudsen effusion apparatus, thermochemical cycles, gas-phase enthalpies, computational organometallic chemistry, medium-sized metal complexes, H2acacen, M(acacen), H2salen, M(salen), Hox, M(ox)2, Hgly, M(gly)2, heterocycle aromatic, gas-phase electron diffraction, intrinsic structure, bidentate ligands, quasi-planar conformation, enthalpy of deprotonation, gaseous-phase glycine, (α)-leucine, L-(α)-isoleucine, L-(α)-phenylglycine, L-(α)-phenylalanine, metal-aminoacid complexes

Thermochemistry of TM(II) Complexes (TM=Ni, Cu and Zn) and Their Ligands from DFT Calculations

Complexes of three transition-metal (TM) cations, Ni(II), Cu(II) and Zn(II), with four different ligands, namely, the tetradentate bis(acetylacetone)ethylenediamine, H2acacen, and bis(salicylidene)ethylenediimine, H2salen, ligands and the bidentate glycine, Hgly, and 8-hydroxyquinoline, Hox, ligands have been studied by means of the density functional theory based B3LYP method and considering all-electron basis sets. The enthalpies of deprotonation and of bond dissociation, at T=298.15 K, of the ligands were calculated and the values are found to be in very good agreement with available experimental data. The calculations were further extended to the standard molar enthalpies of formation in the gas-phase, T = 298.15 K, for the metal complexes by using pertinent working reactions and previously determined experimental enthalpies of formation for key species. Very good agreement was obtained and new values are estimated for the TM(gly)2 and Zn(acacen) complexes. In the cases of the Ni(gly)2 and Cu(gly)2 compounds, new values are suggested. Keywords: Density functional theory, Enthalpy of formation, Enthalpy of bond dissociation, Thermochemistry, Metal complex, Schiff base, Gas-phase acidity, Amino acid, Thermochemistry of TM(II) Complexes, DFT Calculations, transition-metal (TM), bidentate glycine, light-emitting materials, transition metals, Metal complexes, antibacterial, antimalarial, antineoplasic properties, hydroformilation, epoxidation, enthalpies of sublimation, reaction-solution calorimeter, isotenoscopic method, sublimation bulb technique, mass-loss Knudsen effusion apparatus, thermochemical cycles, gas-phase enthalpies, computational organometallic chemistry, medium-sized metal complexes, H2acacen, M(acacen), H2salen, M(salen), Hox, M(ox)2, Hgly, M(gly)2, heterocycle aromatic, gas-phase electron diffraction, intrinsic structure, bidentate ligands, quasi-planar conformation, enthalpy of deprotonation, gaseous-phase glycine, (α)-leucine, L-(α)-isoleucine, L-(α)-phenylglycine, L-(α)-phenylalanine, metal-aminoacid complexes

Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists

A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having ( S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels–Alder reaction of enantiomerically pure imine ( S)- 13, which had been obtained from d-mannitol, with Danishefsky’s Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that ( S, S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4 S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety (( S, S, S)- 5, K i = 28 nM), a fluorine atom (( S, S, S)- 6, WMS-2539, K i = 7 nM) and two fluorine atoms (( S, S)- 7, K i = 48 nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ 1 and σ 2 receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.

Gas-Phase Acid-Base Properties of Melamine and Cyanuric Acid

The thermochemical properties of melamine and cyanuric acid were characterized using mass spectrometry measurements along with computational studies. A triple-quadrupole mass spectrometer was employed with the application of the extended Cooks kinetic method. The proton affinity (PA), gas-phase basicity (GB), and protonation entropy (Δ(p)S) of melamine were determined to be 226.2 ± 2.0 kcal/mol, 218.4 ± 2.0 kcal/mol, and 26.2 ± 2.0 cal/mol K, respectively. The deprotonation enthalpy (Δ(acid)H), gas-phase acidity (Δ(acid)G), and deprotonation entropy (Δ(acid)S) of cyanuric acid were determined to be 330.7 ± 2.0 kcal/mol, 322.9 ± 2.0 kcal/mol, and 26.1 ± 2.0 cal/mol K, respectively. The geometries and energetics of melamine, cyanuric acid, and related ionic species were calculated at the B3LYP/6-31+G(d) level of theory. The computationally predicted proton affinity of melamine (225.9 kcal/mol) and gas-phase deprotonation enthalpy of cyanuric acid (328.4 kcal/mol) agree well with the experimental results. Melamine is best represented as the imide-like triazine-triamine form and the triazine nitrogen is more basic than the amino group nitrogen. Cyanuric acid is best represented as the keto-like tautomer and the N-H group is the most probable proton donor.

Theoretical investigation of the hydrogen bonding interaction between substituted phenols and simple O- and N-bases

The hydrogen bond interaction between substituted phenols (X = NH 2, CH 3, H, Cl, CN, NO 2) and O-bases (HOF, H 2O, CH 3OH, (CH 3) 2O) or N-bases (NHF 2, NH 2F, NH 3, CH 3NH 2) is investigated theoretically at the B3LYP/6-31++G(d,p) level. The calculations include the optimized geometries, the interaction energies, the frequency shifts of the ν(OH) stretching vibration along with relevant NBO parameters such as the charges on the atoms, the occupation of antibonding orbitals and the second-order hyperconjugation energies. The role of both the deprotonation enthalpies of the proton donor O–H bonds of phenols and the proton affinities of the O- or N-bases are explored. The differences between the OH⋯O and OH⋯N hydrogen bonds are outlined.

Experimental and Theoretical Gas-Phase Acidities, Bond Dissociation Energies, and Heats of Formation of HClOx, x = 1−4

Gas-phase deprotonation enthalpies were measured for chloric and perchloric acids and found to be 313.2 +/- 3.3 and 299.9 +/- 5.7 kcal mol(-1), respectively. These values were combined with the previously reported electron affinities of ClO(3) and ClO(4) to obtain BDE(H-OClO(2)) = 97.6 +/- 4.0 kcal mol(-1) and BDE(H-OClO(3)) = 107.4 +/- 6.1 kcal mol(-1). These energetic determinations represent the first measurements of these quantities or extensive revisions of the currently available values. B3LYP, M06, M06-2X, G3, and G3B3 computations also were carried out to provide acidities, electron affinities, bond dissociation energies, and heats of formation via atomization energies for ClO(x) and HClO(x), where x = 1-4. All of the methods do a reasonable job for the first three thermodynamic quantities but only M06 does a satisfactory job for the heats of formation, and its performance is similar to the highly accurate but extremely time intensive W4 method.

The role of conjugative interactions in acidic and basic character of five membered aromatic heterocyclics

The trends in protonation and deprotonation enthalpies for the different potential sites in five membered aromatic heterocyclic molecules have been analysed employing molecular orbital calculations at B3LYP/6311++G∗∗//B3LYP/6-31+G∗, MP2/6-311++G∗∗//MP2/6-31+G∗ and G2MP2 theoretical levels. NBO analysis has been also carried out for the twelve heterocyclic molecules and their protonated and deprotonated species. The reasons for the most basic and acidic site in the molecules under study have been explored in terms of conjugative interactions, electronegativity and charge holding ability of the heteroatoms.

Theoretical investigation of the conformation, acidity, basicity and hydrogen bonding ability of halogenated ethers

MP2/6-311++G(d,p) calculations have been carried out to investigate the conformation, protonation and the hydrogen bonding interactions with water of several halogenated ethers (CH(3)OCH(2)Cl, CH(2)ClOCH(2)Cl, CH(3)OCHCl(2), CHFClOCHF(2)). The optimized geometries, ν(CH) harmonic vibrational frequencies and the SAPT decomposition of the interaction energies are studied. The interaction with one water molecule gives several stable structures characterized by O(w)H(w)...O and CH...O(w) hydrogen bonds or by O...Cl halogen bonding. The MP2/CBS calculated binding energies of different complexes between the halogenated ethers and water vary between 1.7 and 7.7 kcal mol(-1). The energies of these structures are discussed as a function of the proton affinity of the ethers and the deprotonation enthalpy of the CH bonds. The contraction of the CH bonds and blue shifts of the corresponding stretching vibrations in the O-protonated ethers and their O...H(w)O(w) complexes are compared. A natural bond orbital analysis has revealed that substitution of the H atoms by one or several halogen atoms has a great influence on the hyperconjugative effects from the two non-equivalent O lone pairs to relevant antibonding orbitals, and the subsequent geometry of the hydrogen bonded complexes.

Gas-Phase Acidities of Cysteine-Polyglycine Peptides: The Effect of the Cysteine Position

The sequence and conformational effects on the gas-phase acidities of peptides have been studied by using two pairs of isomeric cysteine-polyglycine peptides, CysGly(3,4)NH(2) and Gly(3,4)CysNH(2). The extended Cooks kinetic method was employed to determine the gas-phase acidities using a triple quadrupole mass spectrometer with an electrospray ionization source. The ion activation was achieved via collision-induced dissociation experiments. The deprotonation enthalpies (Delta(acid)H) were determined to be 323.9 +/- 2.5 kcal/mol (CysGly(3)NH(2)), 319.2 +/- 2.3 kcal/mol (CysGly(4)NH(2)), 333.8 +/- 2.1 kcal/mol (Gly(3)CysNH(2)), and 321.9 +/- 2.8 kcal/mol (Gly(4)CysNH(2)), respectively. The corresponding deprotonation entropies (Delta(acid)S) of the peptides were estimated. The gas-phase acidities (Delta(acid)G) were derived to be 318.4 +/- 2.5 kcal/mol (CysGly(3)NH(2)), 314.9 +/- 2.3 kcal/mol (CysGly(4)NH(2)), 327.5 +/- 2.1 kcal/mol (Gly(3)CysNH(2)), and 317.4 +/- 2.8 kcal/mol (Gly(4)CysNH(2)), respectively. Conformations and energetic information of the neutral and anionic peptides were calculated through simulated annealing (Tripos), geometry optimization (AM1), and single point energy calculations (B3LYP/6-31+G(d)), respectively. Both neutral and deprotonated peptides adopt many possible conformations of similar energies. All neutral peptides are mainly random coils. The two C-cysteine anionic peptides, Gly(3,4)(Cys-H)(-)NH(2), are also random coils. The two N-cysteine anionic peptides, (Cys-H)(-)Gly(3,4)NH(2), may exist in both random coils and stretched helices. The two N-cysteine peptides, CysGly(3)NH(2) and CysGly(4)NH(2), are significantly more acidic than the corresponding C-terminal cysteine ones, Gly(3)CysNH(2) and Gly(4)CysNH(2). The stronger acidities of the former may come from the greater stability of the thiolate anion resulting from the interaction with the helix-macrodipole, in addition to the hydrogen bonding interactions.

Gas-Phase Acidities of Cysteine-Polyalanine Peptides I: A3,4CSH and HSCA3,4

The gas-phase acidities of four cysteine-polyalanine peptides, A(3,4)CSH and HSCA(3,4), were determined using the extended Cooks kinetic method with full entropy analysis. A triple-quadrupole mass spectrometer with an electrospray interface was employed for the experimental study. The ion activation was achieved via collision-induced dissociation (CID) experiments. The deprotonation enthalpies (Delta(acid)H) of the peptides were determined to be 332.2 +/- 2.0 kcal/mol (A(3)CSH), 325.9 +/- 2.0 kcal/mol (A(4)CSH), 319.3 +/- 3.0 kcal/mol (HSCA(3)), and 319.2 +/- 4.0 kcal/mol (HSCA(4)). The deprotonation entropies (Delta(acid)S) of the peptides were estimated based on the entropy term (Delta(DeltaS)) and the deprotonation entropies of the reference acids. By using the deprotonation enthalpies and entropies, the gas-phase acidities (Delta(acid)G) of the peptides were derived: 325.0 +/- 2.0 kcal/mol (A(3)CSH), 320.2 +/- 2.0 kcal/mol (A(4)CSH), 316.3 +/- 3.0 kcal/mol (HSCA(3)), and 315.4 +/- 4.0 kcal/mol (HSCA(4)). Conformations and energetic information of the peptides were calculated through simulated annealing (Tripos), geometry optimization (AM1), and single-point energy calculations (B3LYP/6-31+G(d)), respectively. The calculated theoretical deprotonation enthalpies (Delta(acid)H) of 334.2 kcal/mol (A(3)CSH), 327.7 kcal/mol (A(4)CSH), 320.6 kcal/mol (HSCA(3)), and 318.6 kcal/mol (HSCA(4)) are in good agreement with the experimentally determined values. Both the experimental and computational studies suggest that the two N-terminal cysteine peptides, HSCA(3,4), are significantly more acidic than the corresponding C-terminal ones, A(3,4)CSH. The high acidities of the former are likely due to the helical conformational effects for which the thiolate anion may be strongly stabilized by the interaction with the helix macrodipole.

Why Are Esters and Amides Weaker Carbon Acids than Ketones and Acid Fluorides? Contributions by Resonance and Inductive Effects

Two computational methodologies-a vinylogue extrapolation methodology and a block localized wave function (BLW) methodology-were employed to determine the contributions by resonance and inductive effects toward the gas-phase deprotonation enthalpies at the alpha carbons of acetone, acetamide, acetic acid, and acetyl fluoride, which were taken to be model compounds for ketones, amides, esters, and acid fluorides, respectively. Results from the vinylogue methodology suggest that resonance serves to enhance the gas-phase deprotonation enthalpy of a ketone by 34.3 kcal/mol, an amide by 26.2 kcal/mol, an ester by 30.5 kcal/mol, and an acid fluoride by 30.8 kcal/mol. Comparably, the BLW methodology suggests those numbers to be 42.3, 31.2, 36.1, and 39.7 kcal/mol, respectively. Results from the vinylogue methodology suggest that inductive effects serve to enhance the gas-phase deprotonation enthalpy of a ketone by 11.8 kcal/mol, an amide by 12.7 kcal/mol, an ester by 15.5 kcal/mol, and an acid fluoride by 26.0 kcal/mol, and in the same order, those numbers suggested by the BLW methodology are 3.0, 6.2, 8.5, and 16.3 kcal/mol.