New flexible synthesis of pyrazoles with different,functionalized substituents at C3 and C5

Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3 and varying alkyl and aryl substituents attached to carbon 5 are presented. Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at C5 is reported here, starting by coupling protected alkynols with acid chlorides RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5-substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic substitution reactions, the chlorides are useful precursors to other polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)- and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The significance of the ligands made here is that by placing a ligating side chain on a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton will be available for hydrogen bonding, depending on the steric environment created by R at C5.     

Synthesis and structure of ruthenium(IV) complexes featuring N-heterocyclic ligands with an N-H group as the hydrogen-bond donor: hydrogen interactions in solution and in the solid state

The synthesis and characterization of novel ruthenium(IV) complexes [Ru(η(3):η(3)-C(10)H(16))Cl(2)L] [L = 3-methylpyrazole (2b), 3,5-dimethylpyrazole (2c), 3-methyl-5-phenylpyrazole (2d), 2-(1H-pyrazol-5-yl)phenol (2e), 6-azauracile (3), and 1H-indazol-3-ol (4)] are reported. Complex 2e is converted to the chelated complex [Ru(η(3):η(3)-C(10)H(16))Cl(κ(2)-N,O-2-(1H-pyrazol-3-yl)phenoxy)] (5) by treatment with an excess of NaOH. All of the ligands feature N-H, O-H, or C═O as the potential hydrogen-bonding group. The structures of complexes 2a-2c, 2e, 3, and 5 in the solid state have been determined by X-ray diffraction. Complexes 2a-2c and 3, which contain the pyrazole N-H group, exhibit intra- and intermolecular hydrogen bonds with chloride ligands [N-H···Cl distances (?): intramolecular, 2.30-2.78; intermolecular, 2.59-2.77]. Complexes 2e and 3 bearing respectively O-H and C═O groups also feature N-H···O interactions [intramolecular (2e), 2.27 ?; intermolecular (3), 2.00 ?]. Chelated complex 5, lacking the O-H group, only shows an intramolecular N-H···Cl hydrogen bonding of 2.42 ?. The structure of complex 3, which turns out to be a dimer in the solid state through a double intermolecular N-H···O hydrogen bonding, has also been investigated in solution (CD(2)Cl(2)) by NMR diffusion studies. Diffusion-ordered spectroscopy experiments reveal an equilibrium between monomer and dimer species in solution whose extension depends on the temperature, concentration, and coordinating properties of the solvent. Preliminary catalytic studies show that complex 3 is highly active in the redox isomerization of the allylic alcohols in an aqueous medium under very mild reaction conditions (35 °C) and in the absence of a base.     

Synthesis and structure of isomeric palladium(II)-pyrazole chelate complexes with and without an N-H group as hydrogen bond donor

Four new ligands containing a pyrazole ring and either a phosphine or thioether were prepared and converted to their cis-dichloropalladium(II) complexes. Two of the ligands are especially notable for the attachment of a side chain at pyrazole carbon, rather than at nitrogen. The new metal complexes include dichloro[3-(diphenylphosphinomethyl)pyrazole]palladium(II) (1-PdCl2) and dichloro[3-(methylthiomethyl)pyrazole]palladium(II) (2-PdCl2), which both feature an N-H group as a potential proton or hydrogen bond donor. For comparison, isomeric complexes lacking an NH group were prepared: dichloro[1-(diphenylphosphinomethyl)pyrazole]palladium(II) (3-PdCl2) and dichloro[1-(methylthiomethyl)pyrazole]palladium(II) (4-PdCl2). As determined by X-ray crystallography, all four complexes were found to have slightly distorted square planar geometry. Complexes 1-PdCl2 and 2-PdCl2, which contain an NH group, exhibit both intermolecular and intramolecular hydrogen bonding, whereas isomers 3-PdCl2 and 4-PdCl2 do not. Single-crystal X-ray structure determinations on the following compounds are reported: 1-PdCl2, space group P1, a = 8.4488(9) A, b = 8.9175(13) A, c = 12.731(2) A, Z = 2, V = 871.8(2) A3; 2-PdCl2, space group Pbca, a = 10.8827(10) A, b = 11.7721(7) A, c = 14.874(2) A, Z = 8, V = 1905.6 A3; 3-PdCl2, space group P2(1)/c, a = 20.520(2) A, b = 12.549(2) A, c = 13.9784(13) A, Z = 8, V = 3401.1(6) A3; 4-PdCl2, space group Pbca, a = 10.6545(10) A, b = 12.0205(11) A, c = 14.6474(14) A, Z = 8, V = 1875.9(3) A3.     

The empirical correlation between hydrogen bonding strength and excited-state intramolecular proton transfer in 2-pyridyl pyrazoles

A series of 2-pyridyl pyrazoles 1a and 1-5 with various functional groups attached to either pyrazole or pyridyl moieties have been strategically designed and synthesized in an aim to probe the hydrogen bonding strength in the ground state versus dynamics of excited-state intramolecular proton transfer (ESIPT) reaction. The title compounds all possess a five-membered-ring (pyrazole)N-H···N(pyridine) intramolecular hydrogen bond, in which both the N-H bond and the electron density distribution of the pyridyl nitrogen lone-pair electrons are rather directional, so that the hydrogen bonding strength is relatively weak, which is sensitive to the perturbation of subtle chemical substitution and consequently reflected from the associated ESIPT dynamics. Various approaches such as (1)H NMR (N-H proton) to probe the hydrogen bonding strength and absorption titration to assess the acidity-basicity property were made for all the title analogues. The results, together with supplementary support provided by a computational approach, affirm that the increase of acidity (basicity) on the hydrogen bonding donor (acceptor) sites leads to an increase of hydrogen-bonding strength among the title 2-pyridyl pyrazoles. Luminescence results and the associated ESIPT dynamics further reveal an empirical correlation in that the increase of the hydrogen bonding strength leads to an increase of the rate of ESIPT for the title 2-pyridyl pyrazoles, demonstrating an interesting relationship among N-H acidity, hydrogen bonding strength, and the associated ESIPT rate.     

Changes in coordination of sterically demanding hybrid imidazolylphosphine ligands on Pd(0) and Pd(II)

Low-coordinate organometallic complexes are important in structure and catalysis, and hemilability or secondary interactions such as hydrogen bonding enabled by hybrid ligands are receiving increasing attention. To study the factors controlling these phenomena, three new imidazol-2-ylphosphine ligands, L, were made. In these ligands, the bulk around P and the hindrance at the basic and potentially coordinating imidazole N-3 were varied. Remarkably, L(2)Pd(0) complexes 3a-c were shown to be two-coordinate, 12-electron species, despite the availability of imidazole N-3 to enter into eta(2)-P,N chelation. In oxidative additions of C-X bonds to the Pd(0) complexes, reaction rates and products could be controlled by the nature of the C and X groups and the R groups on the phosphine. Most significantly, whereas 4c-PhI and 4c-MeOTf from 3c are normal trans-bis(phosphine)Pd(R)(X) species, 5a-PhI, 5a-PhBr, and 5b-PhI from 3a and 3b were shown by X-ray diffraction to be a monomeric species with a single eta(2)-P,N-chelating phosphine. From 3a and methyl triflate, an ionic complex [6a-Me](+)[OTf](-) with one chelating and one nonchelating phosphine was formed, with temperature-dependent windshield-wiper exchange of the two, showing hemilability. Thus, large phosphine substituents (R = tert-butyl rather than isopropyl) favor chelation. The chelate Pd-imidazole N-3 bond is longer when the heterocyclic nitrogen is hindered by an adjacent tert-butyl group at C-4 (comparing 5a-PhI and 5b-PhI). Finally, whereas in [8b-Ph](+)[OTf](-) from 5b-PhI and isopropylamine, the amine coordinates without chelate opening or hydrogen bonding, in [10c-Me](+)[OTf](-) made from 4c-MeOTf and isopropylamine, the amine is not only coordinated at N but also donates a hydrogen bond to each phosphine imidazol-2-yl substituent.     

The molecular and crystal structure of tert-butyl Nalpha-tert-butoxycarbonyl-L-(S-trityl)cysteinate and the conformation-stabilizing function of weak intermolecular bonding

The title compound, C31H37NO4S [systematic name: (R)-tert-butyl-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoate] is an L-cysteine derivative with three functions: NH2, COOH and SH, blocked by protecting groups tert-butoxycarbonyl, tert-butyl and trityl, respectively. The main chain of the molecule adopts the extended, nearly all-trans C5 conformation with the intramolecular N-H...O=C hydrogen bond. The urethane group is not involved in any intermolecular hydrogen bonding. Only weak intermolecular hydrogen bonds and hydrophobic contacts are observed in the crystal structure. These are C-H...O hydrogen bonds and CH/pi interactions with donor...acceptor distances, C...O ca. 3.5 A and C...C ca. 3.7 A, respectively. The first type of interaction links phenyl H-atoms and carbonyl groups. The second type of interaction is formed between a methyl group of the tert-butyl fragment and a trityl phenyl ring. The resulting molecular conformation in the crystal is very close to an ab initio minimum energy conformer of the isolated molecule. The extended C5 conformation of the main peptide chain is the same and there is slight discrepancy in the disposition of trityl phenyl rings. Their small dislocation creates the possibility of forming the entire network above of extensive, specific, weak intermolecular interactions; these constrain the molecule and permit it to retain the minimum energy C5 conformation of its main chain in the solid state. In contrast, in n-hexane solution, where such specific interactions cannot occur, only a small population of the molecules adopts the extended C5 conformation.     

Blue-emitting platinum(II) complexes bearing both pyridylpyrazolate chelate and bridging pyrazolate ligands: synthesis, structures, and photophysical properties

A new Pt(II) dichloride complex [Pt(fppzH)Cl2] (1), in which fppzH = 3-(trifluoromethyl)-5-(2-pyridyl)pyrazole, was prepared by the treatment of a pyridylpyrazole chelate fppzH with K2PtCl4 in aqueous HCl solution. Complex 1 could further react with its parent pyrazole (pzH), 3,5-dimethylpyrazole (dmpzH), or 3,5-di-tert-butylpyrazole (dbpzH) to afford the monometallic [Pt(fppz)(pzH)Cl] (2), [Pt(fppz)(dmpzH)Cl] (3), [Pt(fppz)(dmpzH)2]Cl (4), or two structural isomers with formula [Pt(fppz)(dbpzH)Cl] (5a,b). Single-crystal X-ray diffraction studies of 2, 4, and 5a,b revealed a square planar Pt(II) framework, among which a strong interligand hydrogen bonding occurred between fppz and pzH ligands in 2. This interligand H-bonding is replaced by dual N-H...Cl interaction in 4 and both intermolecular N-H...O (with THF solvate) and N-H...Cl interaction in 5a,b, respectively; the latter are attributed to the bulky tert-butyl substituents that force the dbpzH ligand to adopt the perpendicular arrangement. Furthermore, complex 2 underwent rapid deprotonation in basic media to afford two isomeric complexes with formula [Pt(fppz)(mu-pz)]2 (6a,b), which are related to each other according to the spatial orientation of the fppz chelates, i.e., trans- and cis-isomerism. Similar reaction exerted on 3 afforded isomers 7a,b. Both 6a,b (7a,b) are essentially nonemissive in room-temperature fluid state but afford strong blue phosphorescence in solid state prepared via either vacuum-deposited thin film or 77 K CH2Cl2 matrix. As also supported by the computational approaches, the nature of emission has been assigned to be ligand-centered triplet pipi* mixed with certain metal-to-ligand charge-transfer character.     

Intramolecular hydrogen bonding in the o-(aminomethyl) phenols

Conclusions The strength of intramolecular hydrogen bonding in the o-(aminomethyl)phenols varies by some 5 kcal/mole, depending on the substituent at the nitrogen atom and in the benzene ring. Steric effects from the substituent determine the bonding strength.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 331–334, February, 1977.     

Rotamer stability in cis-[Pt(diA)G2] complexes (diA = diamine derivative and G = guanine derivative) mediated by carrier-ligand amine stereochemistry as revealed by circular dichroism spectroscopy

Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each guanine leaning towards the cis-G. Such a "six-in" canting of the two guanine ligands can be hampered by the steric interaction between the H8 of each guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of guanine O6 and the cis-amine N-H group. Such a guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each guanine further from the cis-guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.     

Investigating the effect of hydrogen bonding environments in amide cleavage reactions at zinc(II) complexes with intramolecular amide oxygen co-ordination

Amide oxygen co-ordination to a zinc(II) ion around a hydrogen bonding microenvironment is a common structural/functional feature of metalloproteases. We report two strategies to position hydrogen bonding groups in the proximity of a zinc(II)-bound amide oxygen, and we investigate their effect on the stability of the amide group. Polydentate tripodal ligands (6-R1-2-pyridylmethyl)-R2 (R1= NHCOtBu, R2= N(CH2-py-6-X)2 X = H L1, X = NH2, H L2, X = NH2 L3) form [(L)Zn]2+ cations (L =L1, 1; L2, 2; L3, 3) with intramolecular amide oxygen co-ordination (1-3), and intramolecular N-H...O=C(amide) hydrogen bonding (2, 3) rigidly fixed by the ligand framework. 1-3 undergo cleavage of the tert-butyl amide upon addition of Me4NOH.5H2O (1 equiv.) in methanol at 50(1) degrees C. Under these conditions the half-life, t(1/2), of the amide bond is 0.4 h for 1, 9 h for 2 and 320 h for 3. Mononuclear zinc(II) complexes of (6-NHCOtBu-2-pyridylmethyl)-R2(R2= N(CH2CH2)2S) L4 and chelating N2 ligands without hydrogen bonding groups (1,10-phenanthroline L5, 2-(aminomethyl)pyridine L6) as control compounds, and with an amino hydrogen bonding group (6-amino-2-(aminomethyl)pyridine L7) have been synthesised. Amide cleavage is in this case faster at the zinc(II) complex with the amino hydrogen bonding group. Thus, hydrogen bonding environments can both accelerate and slow down amide bond cleavage reactions at zinc(II) sites. Importantly, the magnitude of the effect exerted by the hydrogen bonding environments was found to be significant; 800-fold rate difference. This result highlights the importance of hydrogen bonding environments around metal centres in amide cleavage reactions, which may be relevant to the chemistry of natural metalloproteases and applicable to the design of more efficient artificial protein cleaving agents.     

Coupling of functional hydrogen bonds in pyridoxal-5'-phosphate-enzyme model systems observed by solid-state NMR spectroscopy

We present a novel series of hydrogen-bonded, polycrystalline 1:1 complexes of Schiff base models of the cofactor pyridoxal-5'-phosphate (PLP) with carboxylic acids that mimic the cofactor in a variety of enzyme active sites. These systems contain an intramolecular OHN hydrogen bond characterized by a fast proton tautomerism as well as a strong intermolecular OHN hydrogen bond between the pyridine ring of the cofactor and the carboxylic acid. In particular, the aldenamine and aldimine Schiff bases N-(pyridoxylidene)tolylamine and N-(pyridoxylidene)methylamine, as well as their adducts, were synthesized and studied using 15N CP and 1H NMR techniques under static and/or MAS conditions. The geometries of the hydrogen bonds were obtained from X-ray structures, 1H and 15N chemical shift correlations, secondary H/D isotope effects on the 15N chemical shifts, or directly by measuring the dipolar 2H-15N couplings of static samples of the deuterated compounds. An interesting coupling of the two "functional" OHN hydrogen bonds was observed. When the Schiff base nitrogen atoms of the adducts carry an aliphatic substituent such as in the internal and external aldimines of PLP in the enzymatic environment, protonation of the ring nitrogen shifts the proton in the intramolecular OHN hydrogen bond from the oxygen to the Schiff base nitrogen. This effect, which increases the positive charge on the nitrogen atom, has been discussed as a prerequisite for cofactor activity. This coupled proton transfer does not occur if the Schiff base nitrogen atom carries an aromatic substituent.     

Spectroscopic identification of carbenium and ammonium isomers of protonated aniline (AnH+): IR spectra of weakly bound AnH+ -Ln clusters (L = Ar, N2)

Infrared photodissociation (IRPD) spectra of mass-selected clusters composed of protonated aniline (C6H8N+ = AnH+) and a variable number of neutral ligands (L = Ar, N2) are obtained in the N-H stretch range. The AnH+ -Ln complexes (n < or = 3) are produced by chemical ionization in a supersonic expansion of An, H2, and L. The IRPD spectra of AnH+-Ln feature the unambiguous fingerprints of at least two different AnH+ nucleation centers, namely, the ammonium isomer (5) and the carbenium ions (1 and/or 3) corresponding to protonation at the N atom and at the C atoms in the para and/or ortho positions, respectively. Protonation at the meta and ipso positions is not observed. Both classes of observed AnH+-Ln isomers exhibit very different photofragmentation behavior upon vibrational excitation arising from the different interaction strengths of the AnH+ cores with the surrounding neutral ligands. Analysis of the incremental N-H stretch frequency shifts as a function of cluster size shows that microsolvation of both 5 and 1/3 in Ar and N2 starts with the formation of intermolecular H bonds of the ligands to the acidic NH protons and proceeds by intermolecular pi bonding to the aromatic ring. The analysis of both the photofragmentation branching ratios and the N-H stretch frequencies demonstrates that the N-H bonds in 5 are weaker and more acidic than those in 1/3, leading to stronger intermolecular H bonds with L. The interpretation of the spectroscopic data is supported by density functional calculations conducted at the B3LYP level using the 6-31G* and 6-311G(2df,2pd) basis sets. Comparison with clusters of neutral aniline and the aniline radical cation demonstrates the drastic effect of protonation and ionization on the acidity of the N-H bonds and the topology of the intermolecular potential, in particular on the preferred aromatic substrate-nonpolar ligand recognition motif.     

Estimation on the intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies in glycine and alanine peptides

Computation of accurate intramolecular hydrogen-bonding energies for peptides is of great importance in understanding the conformational stabilities of peptides and developing a more accurate force field for proteins. We have proposed a method to determine the intramolecular seven-membered ring N-H...O=C hydrogen-bonding energies in glycine and alanine peptides. In this article, the method is further applied to evaluate the intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies in peptides. The optimal structures of the intramolecular 10-membered ring N-H...O=C hydrogen bonds in glycine and alanine tripetide molecules are obtained at the MP2 level with 6-31G(d), 6-31G(d,p), and 6-31+G(d,p) basis sets. The intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies are then evaluated based on our method at the MP2/6-311++G(3df,2p) level with basis set superposition error correction. The intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies are calculated to be in the range of -6.84 to -7.66, -4.44 to -4.98, and -6.95 to -7.88 kcal/mol. The method is also applied to estimate the individual intermolecular hydrogen-bonding energies in the dimers of amino-acetaldehyde, 2-amino-acetamide, formamide, and oxalamide, each dimer having two identical intermolecular hydrogen bonds. According to our method, the individual intermolecular hydrogen-bonding energies in the four dimers are calculated to be -1.77, -1.67, -6.35, and -4.82 kcal/mol at the MP2/6-311++G(d,p) level, which are in good agreement with the values of -1.84, -1.72, -6.23, and -4.93 kcal/mol predicted by the supermolecular method.     

The effect of intramolecular interactions on hydrogen bond acidity

DFT calculations on a range of molecules containing intramolecular hydrogen bonds are reported, with a view to establishing how intramolecular hydrogen bonding affects their intermolecular interactions. It is shown that properties such as the energy of the intramolecular H-bond are unrelated to the ability to form external H-bonds. Conversely, several properties of complexes with a reference base correlate well with an experimental scale of H-bond acidity, and accurate predictive models are determined. A more detailed study, using electrostatic and overlap properties of complexes with a reference base, is used to predict the location, as well as strength, of hydrogen bond acidity. The effects of intramolecular hydrogen bonding on acidity can be seen not just on O-H and N-H, where acidity is greatly reduced, but also on certain C-H groups, which in some cases become the primary source of acidity.     

On the competition of the purine bases,functionalities of peptide side chains,and protecting agents for the coordination sites of dicationic cisplatin derivatives

The Pt-L bond energies of simple triammineplatinum(II) complexes, [Pt(NH(3))(3)L](2+), with oxygen-, nitrogen-, and sulfur-containing donor ligands L have been predicted and rationalized using density functional theory. The ligands L have been chosen as models for functionalities of peptide side chains, for sulfur-containing protecting agents, and for adenine and guanine sites of the DNA as the ultimate target of platinum anticancer drugs. Calculation of the Pt-L bond energy in [Pt(NH(3))(3)L](2+) reveals that the soft metal center of triammineplatinum(II) prefers N ligands over S ligands. This remarkable result has been discussed in light of several interpretations of the hard and soft acids and bases principle. The concept of orbital-symmetry-based energy decomposition has been employed for the determination of the contributions from sigma and pi orbital interactions, electrostatics, and intramolecular hydrogen bonding to the Pt-L bond energy. The calculations show that considerable differences in the bond energies of the triammineplatinum(II) complexes with N-heterocycles such as 1-methylimidazole, 9-methyladenine, and 9-methylguanine arise from electrostatics rather than from orbital interactions. Surprisingly, the net stabilization by hydrogen bonding between the (Pt)N-H group and the oxygen of 9-methylguanine is as weak as the intramolecular hydrogen bond in the aqua complex [Pt(NH(3))(3)(H(2)O)](2+), challenging the common hypothesis that DNA-active anticancer drugs require carrier ligands with N-H functionalities because of their hydrogen-bonding ability. The influence of a polarizable environment on the stability of the complexes has been investigated systematically with the dependence of the dielectric constant epsilon. With increasing epsilon, the complexes with S-containing ligands are more strongly stabilized than the complexes of the N-containing heterocycles. At epsilon = 78.4, the dielectric constant of water, 9-methylguanine remains the only purine derivative investigated which is competitive to neutral sulfur ligands. These findings are particularly important for a rationalization of the results from recent experimental studies on the competition of biological donor ligands L for coordination with the metal center of [Pt(dien)L](2+) (dien = 1,5-diamino 3-azapentane).     

Characterization of peptide-pyrazole interactions in solution by low-temperature NMR studies

Complexation of the amino- and carboxyl-protected tripeptide Piv-L-Val-L-Val-L-Val-tBu with 3-methylpyrazole and 3-amino-5-methylpyrazole was studied by low-temperature NMR experiments in a freonic solvent. The peptide forms an extended beta-type structure at all temperatures and associates through hydrogen bonding with the two pyrazole-based beta-sheet ligands. A detailed structural characterization of the formed complexes by one- and two-dimensional NMR experiments under slow exchange conditions was made possible by employing very low temperatures. The tripeptide associates to stable antiparallel dimers that are symmetrically capped on both sides by two pyrazole receptors to form 2:2 complexes. Amide groups of two neighboring residues in an extended conformation are involved in cyclic hydrogen bonds to the pyrazole. Based on amide chemical shift changes, the relative strength of intermolecular hydrogen bonds can be assessed and correlated with the electronic effects of the substituents on the pyrazole.     

A 13C n.m.r. study of the B6 vitamins and of their aldimine derivatives

The vitamins, pyridoxine, pyridoxal, pyridoxamine, pyridoxal-5′-phosphate and pyridoxamine-5′-phosphate, have been studied in aqueous solution over a pH range of 2–12 by ¹³C nuclear magnetic resonance spectroscopy. Resonance assignments are made primarily by the spin–spin coupling constants of carbons with protons and with phosphorus. The proton–carbon coupling constants show a marked conformational dependence in the hemiacetal form of pyridoxal. Furthermore, the H-6? C-5 coupling constant in the vitamins is much smaller than the corresponding constant in pyridine. This may be due either to an effect of the C-5 substituent in vitamins or to a different electronic configuration of the zwitterionic hydroxypyridine ring. The addition of manganese to a solution of pyridoxal phosphate causes line broadenings consistent with the interaction of the metal ion with this vitamin at the formyl and phenolic oxygens. The chemical shifts of the aromatic carbons of pyridoxine have been calculated, as a function of pH, by summing shielding parameters which were estimated empirically from pyridine derivatives. The calculated shifts agree well with the experimental data for C-3, C-5 and C-6, less well for C-2, and poorly for C-4. The deviation from additivity for C-4 indicates a preferred orientation for the 4-hydroxymethyl substituent caused by internal hydrogen bonding between the substituents at C-3 and C-4. Evidence is presented for the existence of the free aldehyde form of pyridoxal at alkaline pH. Aldimine complexes of pyridoxal and pyridoxal phosphate with amines and amino acids have also been studied. Characteristic chemical shift changes caused by both pyridinium and aldimine nitrogen deprotonations are seen. Additionally, the chemical shifts of carbons of the pyridine ring are dependent upon the structure of the imine, especially when the aldimine nitrogen is protonated. We conclude that this dependency is due to steric effects in an aldimine complex which is constrained by internal hydrogen bonding. We also discuss the merits of carbons 3 and 4 as possible sites of cofactor labeling for enzymatic studies.     

Stabilization of copper(II) thiosulfonate coordination complexes through cooperative hydrogen bonding interactions

A series of copper(II) thiosulfonate complexes have been prepared via the reaction of [Cu(Me 3tren)(OH 2)](ClO 4) 2 (Me 3tren = tris(2-methylaminoethyl)amine) with three thiosulfonate ligands (RSO 2S (-), where R = Me, Ph, and MePh) and characterized by microanalysis, FTIR spectroscopy, and X-ray crystallography. In these complexes, the distorted trigonal bipyramidal copper(II) coordination sphere is occupied by four amine nitrogen atoms from the tripodal tetramine ligand and an apically bound sulfur atom from the thiosulfonate ligand. By using the tripodal tetramine ligand the oxidation of the thiosulfonate has been restricted, allowing the isolation of the complexes. The Cu-S distances were found to be similar to those in related thiosulfate complexes, indicating coordinative interactions of similar strength. Two types of intramolecular hydrogen bonding interactions were evident which enhance the binding of the thiosulfonate to the copper(II) center. These interactions, which involve two amine N-H groups and either one or two thiosulfonate oxygens, were found to be weaker than in the corresponding thiosulfate complexes. The complex formation constants for the thiosulfonate complexes (log K f = 0.3-0.7) were found to be two orders of magnitude lower than compared to the thiosulfate analogues. This correlates well with a lower strength of intramolecular hydrogen bonding.     

Photochemistry of hydrogen bonded heterocycles probed by photodissociation experiments and ab initio methods

In this perspective article, we focus on the photochemistry of five-membered nitrogen containing heterocycles (pyrrole, imidazole and pyrazole) in clusters. These heterocycles represent paradigmatic structures for larger biologically active heterocyclic molecules and complexes. The dimers of the three molecules are also archetypes of different bonding patterns: N-H···π interaction, N-H···N hydrogen bond and double hydrogen bond. We briefly review available data on photochemistry of the title molecules in the gas phase, but primarily we focus on the new reaction channels opened upon the complexation with other heterocycles or solvent molecules. Based on ab initio calculations we discuss various possible reactions in the excited states of the clusters: (1) hydrogen dissociation, (2) hydrogen transfer between the heterocyclic units, (3) molecular ring distortion, and (4) coupled electron-proton transfer. The increasing photostability with complexity of the system can be inferred from experiments with photodissociation in these clusters. A unified view on photoinduced processes in five-membered N-heterocycles is provided. We show that even though different deactivation channels are energetically possible for the complexed heterocycles, in most cases the major result is a fast reconstruction of the ground state. The complexed or solvated heterocycles are thus inherently photostable although the stability can in principle be achieved via different reaction routes.     

Interactions between brushlike polyacrylic acid side chains on a polyacrylate backbone in dioxane-water.

Densely grafted polyacrylic acids (d-PAAs) with overcrowded PAA side chains on the polyacrylate main chains were synthesized and characterized. Acryloyl poly(tert-butyl acrylate) macromonomer [M-P(tert-BA)] was prepared with a definite chain length (n=29) by atom-transfer radical polymerization (ATRP), then homopolymerization was carried out to produce densely grafted P(tert-BA)s with polyacrylate main chains of two different lengths (m=27 and 161). The two d-PAAs were obtained by hydrolyzing d-P(tert-BA)s in the presence of trifluoroacetic acid (TFA). The d-PAAs exhibit intermolecular and intramolecular hydrogen bonding between the carboxylic groups of PAA side chains in dioxane and pyridine; both were investigated using proton nuclear magnetic resonance (1H NMR) spectroscopy. The intermolecular hydrogen bonding was found to be dependent on polymer concentration, temperature, and water content. The intramolecular association between the PAA side chains was found to produce a contraction of the hydrodynamic volume of the d-PAA. Intermolecular hydrogen bonding produces aggregates, as demonstrated by dynamic light scattering (DLS). The clusters were found to shrink as the overall water concentration decreased, and this effect is tentatively explained by considering the gradient in chemical potential of water inside the clusters in comparison with the solvent phase.