Investigating the influence of the sulfur oxidation state on solid state conformation

Design, synthesis and structural characterization of a series of diphenylacetylene derivatives bearing organosulfur, amide and amine moieties has been achieved in which the molecular conformation is controlled through variation of the hydrogen bond properties on alteration of the oxidisation level of sulfur.

Crystal engineering: exploiting variation of sulfur oxidation for the control of the solid state structure of organosulfur compounds

This thesis is focused on the design and synthesis of a diverse range of novel organosulfur compounds (sulfides, sulfoxides and sulfones), with the objective of studying their solid state properties and thereby developing an understanding of how the molecular structure of the compounds impacts upon their solid state crystalline structure. In particular, robust intermolecular interactions which determine the overall structure were investigated. These synthons were then exploited in the development of a molecular switch. Chapter One provides a brief overview of crystal engineering, the key hydrogen bonding interactions utilized in this work and also a general insight into “molecular machines” reported in the literature of relevance to this work. Chapter Two outlines the design and synthetic strategies for the development of two scaffolds suitable for incorporation of terminal alkynes, organosulfur and ether functionalities, in order to investigate the robustness and predictability of the S=O•••H-C≡C- and S=O•••H-C(α) supramolecular synthons. Crystal structures and a detailed analysis of the hydrogen bond interactions observed in these compounds are included in this chapter. Also the biological activities of four novel tertiary amines are discussed. Chapter Three focuses on the design and synthesis of diphenylacetylene compounds bearing amide and sulfur functionalities, and the exploitation of the N-H•••O=S interactions to develop a “molecular switch”. The crystal structures, hydrogen bonding patterns observed, NMR variable temperature studies and computer modelling studies are discussed in detail. Chapter Four provides the overall conclusions from chapter two and chapter three and also gives an indication of how the results of this work may be developed in the future. Chapter Five contains the full experimental details and spectral characterisation of all novel compounds synthesised in this project, while details of the NCI (National Cancer Institute) biological test results are included in the appendix.

A vibrational spectroscopic investigation of rhodanine and its derivatives in the solid state

Raman and infrared spectra are reported for rhodanine, 3-aminorhodanine and 3-methylrhodanine in the solid state. Comparisons of the spectra of non-deuterated/deuterated species facilitate discrimination of the bands associated with N-H, NH2, CH2 and CH3 vibrations. DFT calculations of structures and vibrational spectra of isolated gas-phase molecules, at the B3-LYP/cc-pVTZ and B3-PW91/cc-pVTZ level, enable normal coordinate analyses in terms of potential energy distributions for each vibrational normal mode. The cis amide I mode of rhodanine is associated with bands at ~ 1713 and 1779 cm-1, whereas a Raman and IR band at ~ 1457 cm-1 is assigned to the amide II mode. The thioamide II and III modes of rhodanine, 3-aminorhodanine and 3-methylrhodanine are observed at 1176 and 1066/1078; 1158 and 1044; 1107 and 984 cm-1 in the Raman and at 1187 and 1083; 1179 and 1074; 1116 and 983 cm-1 in the IR spectra, respectively.

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.

Vibrational spectroscopic studies of the structure of di-amino acid peptides. Part II: cyclo(L-Asp-L-Asp) in the solid state and in aqueous solution

Solid-state protonated and N,O-deuterated Fourier transform infrared (IR) and Raman scattering spectra together with the protonated and deuterated Raman spectra in aqueous solution of the cyclic di-amino acid peptide cyclo(L-Asp-L-Asp) are reported. Vibrational band assignments have been made on the basis of comparisons with previously cited literature values for diketopiperazine (DKP) derivatives and normal coordinate analyses for both the protonated and deuterated species based upon DFT calculations at the B3-LYP/cc-pVDZ level of the isolated molecule in the gas phase. The calculated minimum energy structure for cyclo(L-Asp-L-Asp), assuming C-2 symmetry, predicts a boat conformation for the DKP ring with both the two L-aspartyl side chains being folded slightly above the ring. The C=O stretching vibrations have been assigned for the side-chain carboxylic acid group (e.g. at 1693 and 1670 cm(-1) in the Raman spectrum) and the cis amide I bands (e.g. at 1660 cm(-1) in the Raman spectrum). The presence of two bands for the carboxylic acid C=O stretching modes in the solid-state Raman spectrum can be accounted for by factor group splitting of the two nonequivalent molecules in a crystallographic unit cell. The cis amide II band is observed at 1489 cm(-1) in the solid-state Raman spectrum, which is in agreement with results for cyclic di-amino acid peptide molecules examined previously in the solid state, where the DKP ring adopts a boat conformation. Additionally, it also appears that as the molecular mass of the substituent on the C-alpha atom is increased, the amide II band wavenumber decreases to below 1500 cm(-1); this may be a consequence of increased strain on the DKP ring. The cis amide II Raman band is characterized by its relatively small deuterium shift (29 cm(-1)), which indicates that this band has a smaller N-H bending contribution than the trans amide II vibrational band observed for linear peptides.

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 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.

The implementation of FT-Raman spectroscopy to study solid state moisture induced changes in the crystallographic nature of pharmaceutical excipients - a lesson in humidity

An aqueous solution of sucrose was lyophilised, producing amorphous sucrose. This wasthen stored under different humidity at 25ºC for 1 week, allowing some samples tocrystallise. FT-Raman spectroscopy and PXRD have been successfully shown toqualitatively distinguish between amorphous and crystalline samples of sucrose. The datafrom the two techniques is complementary.

Liquid and solid-state structures of 1,3-dimethylimidazolium salts

Using neutron and single crystal X-ray diffraction the structures of 1,3-dimethylimidazolim chloride and hexafluorophosphate salts have been determined in the liquid and the solid-state. The relative hydrogen bonding characteristics and sizes of the two anions force the ions to pack differently. In each case, a strong correlation between the crystal structure and liquid structure is found.

Evolution of Clay Morphology in Polypropylene/Montmorillonite Nanocomposites upon Equi-biaxial Stretching: A Solid-State NMR and TEM Approach

Solid-state NMR and TEM were used to quantitatively examine the evolution of clay morphology upon equibiaxial stretching of polypropylene/montmorillonite (PP-MMT) nanocomposites up to a stretch ratio (?= final length/initial length) of 3.5. 1 H spin-lattice relaxation times were measured by the saturation-recovery sequence. For the nanocomposites, initial portions of the magnetization recovery
curves (e~20 ms) were found to depend on v t, indicative of diffusion-limited relaxation and in agreement with calculations based on estimates of the spin-diffusion barrier radius surrounding the paramagnetic centers in the clay, the electron-nucleus coupling constant, and the spin-diffusion coefficient. Initial slopes of these magnetization recovery curves directly correlated with the fraction of clay/polymer interface. New clay surface was exposed as a near linear function of strain. Long-time portions of the magnetization recovery curves yielded information on the average interparticle separations, which decreased slowly before reaching a plateau at ?=~2.5 as particles aligned. TEM images supported these findings and were used to define and quantify degrees of exfoliation and homogeneity from the NMR data. Exfoliation, defined as (platelets/ stack)-1, increased from 0.38 (unstretched) to 0.80 at ? = 3.5 for PP-MMT nanocomposites stretched at
150 C and 16 s-1. A lower stretch temperature, 145 C, which is slightly below melting onset, led to an exfoliation degree of 0.87 at ?= 2.8, consistent with the ability of higher melt viscosities to allow for higher shear stress transfer. Exposure of new clay surface is attributed to aggregate breakup and orientation at low strains (? e ~2) and to platelets sliding apart at higher strains.

Solid-state analysis of low-melting 1,3-dialkylimidazolium hexafluorophosphate salts (ionic liquids) by combined x-ray crystallographic and computational analyses

The interactions of ions in the solid state for a series of representative 1,3-dialkylimidazolium hexafluorophosphate salts (either ionic liquids or closely related) have been examined by crystallographic analysis, combined with the theoretical estimation of crystal-packing densities and lattice-interaction energies. Efficient close-packing of the ions in the crystalline states is observed, but there was no compelling evidence for specific directional hydrogen-bonding to the hexafluorophosphate anions or the formation of interstitial voids. The close-packing efficiency is supported by the theoretical calculation of ion volumes, crystal lattice energies, and packing densities, which correlated well with experimental data. The crystal density of the salts can be predicted accurately from the summation of free ion volumes and lattice energies calculated. Of even more importance for future work, on these and related salts, the solid-state density of 1,3-dialkylimidazolium hexafluorophosphate salts can be predicted with reasonable accuracy purely on the basis of on ab initio free ion volumes, and this allows prediction of lattice energies without necessarily requiring the crystal structures.