pKa values of aqua ligands of platinum (II) anticancer complexes: [1H, 15N] and 195Pt NMR Studies of cis- and trans- [PtCl2 (NH3) (Cyclohexylamine)]

Syntheses and NMR studies are reported of two 15N-labelled Pt(II) complexes of anticancer interest: cis-PtCl2(15NH3)(c-C6H1115NH2), a metabolite of the orally-active Pt(IV) complex cis,trans,cis-[PtCl2(acetate)2(c-C6H11NH2)(NH3), and trans-[PtCl2(15NH3)(c-C6H1115NH2), a reduction product of the active Pt(IV) complex trans,trans,trans-[PtCl2(OH)2(c-C6H11NH2). For cis-[PtCl2(15NH3)(c-C6H1115NH2), hydrolysis was faster for the chloride ligand trans to cyclohexylamine, and the pKa values determined by [1H, 15N NMR spectroscopy for the two cis monoaqua isomers were the same (6.73). The trans monoaqua complex was a stronger acid with pKa of 5.4 (determined by 195Pt NMR). For the cis diaqua complex, pKa values of 5.68 and 7.68 were determined.

Can density functional theory (DFT) be used as an aid to a deeper understanding of tandem mass spectrometric fragmentation pathways?

Prediction of tandem mass spectrometric (MS/MS) fragmentation for non-peptidic molecules based on structure is of immense interest to the mass spectrometrist. If a reliable approach to MS/MS prediction could be achieved its impact within the pharmaceutical industry could be immense. Many publications have stressed that the fragmentation of a molecular ion or protonated molecule is a complex process that depends on many parameters, making prediction difficult. Commercial prediction software relies on a collection of general heuristic rules of fragmentation, which involve cleaving every bond in the structure to produce a list of 'expected' masses which can be compared with the experimental data. These approaches do not take into account the thermodynamic or molecular orbital effects that impact on the molecule at the point of protonation which could influence the potential sites of bond cleavage based on the structural motif. A series of compounds have been studied by examining the experimentally derived high-resolution MS/MS data and comparing it with the in silico modelling of the neutral and protonated structures. The effect that protonation at specific sites can have on the bond lengths has also been determined. We have calculated the thermodynamically most stable protonated species and have observed how that information can help predict the cleavage site for that ion. The data have shown that this use of in silico techniques could be a possible way to predict MS/MS spectra. Copyright (C) 2009 John Wiley & Sons, Ltd.

Low temperature crystal structure of N-Acetyl-L-Glutamic acid: comparison with the DFT calculated structure

N-acetyl-L-glutamic acid, crystallizes in the orthorhombic space group P2(1)2(1)2(1) with unit cell parameters a = 4.747(3), b = 12.852(7), c = 13.906(7) Å, V = 848.5(8) Å3, Z = 4, density (calculated) = 1.481 mg/m3, linear absorption coefficient 0.127 mm−1. The crystal structure determination was carried out with MoKalpha X-ray data measured with liquid nitrogen cooling at 100(2) K temperature. In the final refinement cycle the data/restraints/parameter ratios were 1,691/0/131; goodness-of-fit on F(2) = 1.122. Final R indices for [I > 2sigma(I)] were R1 = 0.0430, wR2 = 0.0878 and R indices (all data) R1 = 0.0473, wR2 = 0.0894. The largest electron density difference peak and hole were 0.207 and −0.154 eÅ(−3). Details of the molecular geometry are discussed and compared with a model DFT structure calculated using Gaussian 98.

Vibrational spectroscopy and DFT calculations of the di-amino acid peptide L-aspartyl-L-glutamic acid in the zwitterionic state

Solid state IR and Raman as well as aqueous solution state Raman spectra are reported for the linear di-amino acid peptide L-aspartyl-L-glutamic acid (L-Asp-L-Glu); the solution state Raman spectrum has also been obtained for the N,O-deuterated derivative. SCF-DFT calculations at the B3-LYP/cc-pVDZ level established that the structure and vibrational spectra of L-Asp-L-Glu can be interpreted using a model of the peptide with ten hydrogen-bonded water molecules, in conjunction with the conductor-like polarizable continuum solvation method. The DFT calculations resulted in the computation of a stable zwitterionic structure, which displays trans-amide conformation. The vibrational spectra were computed at the optimised molecular geometry, enabling normal coordinate analysis, which yielded satisfactory agreement with the experimental IR and Raman data. Computed potential energy distributions of the normal modes provided detailed vibrational assignments.

Vibrational spectroscopy and DFT calculations of di-amino acid cyclic peptides. Part I: cyclo(Gly-Gly), cyclo(L-Ala-L-Ala) and cyclo(L-Ala-Gly) in the solid state and in aqueous solution

Investigations of the vibrational spectra of cyclo(Gly-Gly), cyclo(L-Ala-L-Ala) and cyclo(t-Ala-Gly) are reported. Raman scattering and Fourier transform infrared (FTIR) spectra of solid-state and aqueous protonated samples, as well as their corresponding N-deuterated isotopomers, have been examined. In addition, density functional theory (DFT) (B3-LYP/cc-pVDZ) calculations of molecular structures and their associated vibrational modes were carried out. In each case, the calculated structures of lowest energy for the isolated gas-phase molecules have boat conformations. Assignments have been made for the observed Raman and FTIR vibrational bands of the cyclic di-amino acid peptides (CDAPs) examined. Raman polarization studies of aqueous phase samples are consistent with C-2 and C-1 symmetries for the six-membered rings of cyclo(L-Ala-L-Ala) and cydo(L-Ala-Gly), respectively. There is a good correlation between experimental and calculated vibrational bands for the three CDAPs. These data are in keeping with boat conformations for cydo(L-Ala-L-Ala) and cyclo(L-Ala-Gly) molecules, predicted by the ab initio calculations, in both the solid and aqueous solution states. However, Raman spectroscopic results might infer that cyclo(L-AlaGly) deviates only slightly from planarity in the solid state. The potential energy distributions of the amide I and II modes of a cis-peptide linkage are shown to be significantly different from those of the trans-peptides. For example, deuterium shifts have shown that the cis-amide I vibrations found in cyclo(Gly-Gly), cyclo(L-Ala-L-Ala), and cyclo(L-Ala-Gly) have larger N-H contributions compared to their trans-amide counterparts. Compared to trans-amide II vibrations, cis-amide II vibrations show a considerable decrease in N-H character.

IR/Raman spectroscopy and DFT calculations of cyclic di-amino acid peptides. Part III: comparison of solid state and solution structures of cyclo(L-Ser-L-Ser)

B3-LYP/cc-pVDZ calculations of the gas-phase structure and vibrational spectra of the isolated molecule cyclo(L-Ser-L-Ser), a cyclic di-amino acid peptide (CDAP), were carried out by assuming C-2 symmetry. It is predicted that the minimum-energy structure is a boat conformation for the diketopiperazine (DKP) ring with both L-Beryl side chains being folded slightly above the ring. An additional structure of higher energy (15.16 kJ mol(-1)) has been calculated for a DKP ring with a planar geometry, although in this case two fundamental vibrations have been calculated with imaginary wavenumbers. The reported X-ray crystallographic structure of cyclo(L-Ser-L-Ser), shows that the DKP ring displays a near-planar conformation, with both the two L-Beryl side chains being folded above the ring. It is hypothesized that the crystal packing forces constrain the DKP ring in a planar conformation and it is probable that the lower energy boat conformation may prevail in the aqueous environment. Raman scattering and Fourier-transform infrared (FT-IR) spectra of solid state and aqueous solution samples of cyclo(L-Ser-L-Ser) are reported and discussed. Vibrational band assignments have been made on the basis of comparisons with the calculated vibrational spectra and band wavenumber shifts upon deuteration of labile protons. The experimental Raman and IR results for solid-state samples show characteristic amide I vibrations which are split (Raman:1661 and 1687 cm(-1), IR:1666 and 1680 cm(-1)), possibly due to interactions between molecules in a crystallographic unit cell. The cis amide I band is differentiated by its deuterium shift of ~ 30 cm(-1), which is larger than that previously reported for trans amide I deuterium shifts. A cis amide II mode has been assigned to a Raman band located at 1520 cm(-1). The occurrence of this cis amide II mode at a wavenumber above 1500 cm(-1) concurs with results of previously examined CDAP molecules with low molecular weight substituents on the C-alpha atoms, and is also indicative of a relatively unstrained DKP ring.

Vibrational spectra and crystal structure of the di-amino acid peptide cyclo(L-Met-L-Met): Comparison of experimental data and DFT calculations

Experimental Raman and FT-IR spectra of solid-state non-deuterated and N-deuterated samples of cyclo(L-Met-L-Met) are reported and discussed. The Raman and FT-IR results show characteristic amide I vibrations (Raman: 1649 cm-1, infrared: 1675 cm-1) for molecules exhibiting a cis amide conformation. A Raman band, assigned to the cis amide II vibrational mode, is observed at sim1493 cm-1 but no IR band is observed in this region. Cyclo(L-Met-L-Met) crystallises in the triclinic space group P1 with one molecule per unit cell. The overall shape of the diketopiperazine (DKP) ring displays a (slightly distorted) boat conformation. The crystal packing employs two strong hydrogen bonds, which traverse the entire crystal via translational repeats. B3-LYP/cc-pVDZ calculations of the structure of the molecule predict a boat conformation for the DKP ring, in agreement with the experimentally determined X-ray structure. Copyright © 2009 John Wiley & Sons, Ltd.

DFT calculations of the structures and vibrational spectra of the [Fe(bpy)(3)](2+) and [Ru(bpy)(3)](2+) complexes

Structures of the [M(bpy)(3)](2+) complexes (M = Fe and Ru) have been calculated at the B3-LYP/DZVP level. IR and Raman spectra were calculated using the optimised geometries, employing a scaled quantum chemical force field, and compared with an earlier normal coordinate analysis of [Ru(bpy)(3) ](2+) which was based upon experimental data alone, and the use of a simplified model. The results of the calculations provide a highly satisfactory fit to the experimental data and the normal coordinate analyses, in terms of potential energy distributions, allow a detailed understanding of the vibrational spectra of both complexes. Evidence is presented for Jahn-Teller distortion in the E-1 MLCT excited state. (C) 2008 Elsevier B.V. All rights reserved.

Vibrational spectra of α-amino acids in the zwitterionic state in aqueous solution and the solid state: DFT calculations and the influence of hydrogen bonding

The zwitterionic forms of the two simplest alpha-amino acids, glycine and l-alanine, in aqueous solution and the solid state have been modeled by DFT calculations. Calculations of the structures in the solid state, using PW91 or PBE functionals, are in good agreement with the reported crystal structures, and the vibrational spectra computed at the optimized geometries provide a good fit to the observed IR and Raman spectra in the solid state. DFT calculations of the structures and vibrational spectra of the zwitterions in aqueous solution at the B3-LYP/cc-pVDZ level were found to require both explicit and implicit solvation models. Explicit solvation was modeled by inclusion of five hydrogen-bonded water molecules attached to each of the five possible hydrogen-bonding sites in the zwitterion and the integration equation formalism polarizable continuum model (IEF-PCM) was employed, providing a satisfactory fit to observed IR and Raman spectra. Band assignments are reported in terms of potential-energy distributions, which differ in some respects to those previously reported for glycine and l-alanine.

Co-acquisition of hyperpolarised 13C and 15N NMR spectra

Recent developments in dynamic nuclear polarisation now allow significant enhancements to be generated in the cryo solid state and transferred to the liquid state for detection at high resolution. We demonstrate that the Ardenkjaer-Larsen method can be extended by taking advantage of the properties of the trityl radicals used. It is possible to hyperpolarise 13C and 15N simultaneously in the solid state, and to maintain these hyperpolarisations through rapid dissolution into the liquid state. We demonstrate the almost simultaneous measurement of hyperpolarised 13C and hyperpolarised 15N NMR spectra. The prospects for further improvement of the method using contemporary technology are also discussed.

Applications of DNP-NMR for the measurement of heteronuclear T1 relaxation times

Measurement of heteronuclear spin-lattice relaxation times is hampered by both low natural abundance and low detection sensitivity. Combined with typically long relaxation times, this results in extended acquisition times which often renders the experiment impractical. Recently a variant of dynamic nuclear polarisation has been demonstrated in which enhanced nuclear spin polarisation, generated in the cryo-solid state, is transferred to the liquid state for detection. Combining this approach with small flip angle pulse trains, similar to the FLASH-T(1) imaging sequence, allows the rapid determination of spin-lattice relaxation times. In this paper we explore this method and its application to the measurement of T(1) for both carbon-13 and nitrogen-15 at natural abundance. The effects of RF inhomogeneity and the influence of proton decoupling in the context of this experiment are also investigated.