Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / Supramolecular synthesis relies upon the creative and rational use of the common intermolecular forces and a proper understanding of these forces is critical for design and assembly of molecular building blocks into extended networks. The strength of seven substituted pyridines as hydrogen-bond acceptors was probed using a series of fifteen mono/dicarboxylic acids to demonstrate the interrelationship between the charge on the substrate and its ability to form co-crystals/salts. The higher charge in the acceptor led to proton transfer (100% yield) from the hydrogen bond donor to give a salt, whereas the lower charge led to co-crystals. This specificity observed for small molecules was extended to an investigation of selectivity in ditopic molecules. A series of nineteen hydrogen-bond donors, including fifteen carboxylic acids and four cyanoximes, were tested for binding preferences against ten ditopic ligands with variable charges. The overall supramolecular yield of 82% (9/11) proved a high degree of reliability in terms of best acceptor/donor approach, hence establishing the efficiency of the calculated charges as a guideline for molecular recognition processes. Solubility and thermal properties of pharmaceutical drug mimics were altered via formation of co-crystals/salts. The ligands and their co-crystals/salts with five even-chain dicarboxylic acids were synthesized and their comparative solubility in pure water and in pH 6.8 buffer solution measured. Solubility enhancement to a degree of 9x is observed for pharmaceutical drug haloperidol, whereas decrease in solubility down to 81% is achieved for 2-amino-5-(3-pyridyl)pyrimidine (which has agrochemical significance). Also the thermal and solubility behavior of these co-crystals were shown to reflect the properties of their parent co-crystallizing agents, allowing for a modulation of physical properties. Finally, the specificity and selectivity of the intermolecular interactions observed for small molecules were applied in the synthesis of hydrogen and halogen-bonded capsules. Several resorcinarene-based cavitands were synthesized and their upper rim decorated with acetamidopyridyl, aminopyrazinyl, 3-pyridyl, and 4-pyridyl moieties with hydrogen and halogen-bonding potentials. A homomeric hydrogen-bonded capsule was formed with self-assembly of acetamidoethynylcavitand via N-H···O=C interactions, whereas a heteromeric halogen-bonded capsule, the very first of its kind, was formed with N···I halogen-bonded interaction between 3-pyridylcavitand and tetrafluoroiodo-substituted calixarene.

This work describes the design and synthesis of a set of four organic molecules that are intended to hydrogen-bond to each other in a pairwise manner. The four hydrogen-bonding units, termed ‘A’, ‘B’, ‘C’ and ‘D’, when placed in solution together, are designed so that A binds only to B, and C binds only to D. Each unit does not bind to itself, nor to either of the other two units to which binding is not intended. For example, A binds to B, but not to A, C, or D. Each unit contains an array of four hydrogen-bonds for strong binding to its partner, is designed to be as rigid as possible, as non-tautomeric as possible, and utilises a staggered non-symmetrical architecture. Of the four intended compounds, three were successfully synthesised (A, B and D). Units B and D were soluble in CDCl₃, but Unit A was not. Therefore, the design and synthesis of Unit A was amended, and two variants of Unit A that are both soluble in CDCl₃ were successfully synthesised. ¹H NMR binding experiments were performed between Unit B and each of the two variants of Unit A. Their binding behaviour was described. A binding constant could not be calculated because the units did not bind in a 1:1 fashion.

Thesis (MSc (Chemistry and Polymer Science))--Stellenbosch University, 2008. / Please refer to full text to view abstract.

Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: This study aimed to combine the principles of crystal engineering with the properties of cyclotriphosphazene derivatives to construct supramolecular assemblies in the solid state. The ease with which the chloro substituents on cyclotriphosphazenes can be replaced makes them ideal candidates for this study. The substituents were chosen for their ability to form either hydrogen bonding interactions or halogen bonding interactions in the solid state. The cyclotriphosphazene derivatives were co-crystallised with various small organic molecules with complementary functional groups, as well as with other cyclophosphazene derivatives. The aim was to form co-crystals or solvates with these cyclophosphazene derivatives as co-crystals contain a wealth of information regarding the forces governing the aggregation of molecules in the solid state. Cyclotriphosphazenes, with their array of substituents, could broaden the range of potential interactions governing crystalline assembly. Fifteen cyclotriphosphazene derivatives were synthesised and characterised in this study. The novel crystal structures of two cyclotriphosphazene derivatives have been elucidated by single crystal X-ray diffraction. These are 2,2-bis(4-formylphenoxy)-4,4,6,6-bis[spiro(2',2"-dioxy-1',1"-biphenylyl)]cyclotriphosphazene and hexakis(4-cyano-phenoxy)cyclotriphosphazene. In the course of this study two novel polymorphs of hexakis(4-fluorophenoxy)cyclotri-phosphazene were identified and studied. The novel triclinic form undergoes an irreversible transformation to the previously reported monoclinic phase at high temperatures. The reported monoclinic phase, however, transforms to a monoclinic C phase in a single-crystal to single-crystal fashion. It is also suspected that this phase transformation is in fact reversible on cooling of the crystal to temperatures below -45 °C. One novel co-crystal structure of hexakis(4-pyridyloxy)cyclotriphosphazene with terephthalic acid was identified and characterised. However, analysis of the Cambridge Structural Database indicates that co-crystal formation with cyclophosphazenes is not a commonly occurring phenomenon. This leads to the conclusion that cyclotriphosphazenes can be used in crystal engineering as supramolecular building blocks, but their shape and size tend to inhibit the formation of co-crystals. Therefore co-crystal formers have to be chosen with great care. / AFRIKAANSE OPSOMMING: Die doel van hierdie studie was om die beginsels van kristalingenieurswese te kombineer met die eienskappe van siklotrifosfaseen afgeleides om sodoende supramolekulêre versamelings in die vastetoestand te bou. Die gemak waarmee die chloor substituente op die siklotrifosfaseenring vervang kan word, maak hierdie molekules ideaal vir hierdie studie. Die substituente is gekies op grond van hul potensiaal om waterstofbindings of intermolekulêre halogeenbindings in die vastetoestand te vorm. Ko-kristallisasie eksperimente is met die siklotrifosfaseen afgeleides en verskeie klein organiese molekules met komplementêre funksionele groepe uitgevoer, asook tussen die verskeie siklotrifosfaseen afgeleides met mekaar. Die doel was om mede-kristalle of solvate met hierdie siklotrifosfaseen afgeleides te vorm aangesien mede-kristalle ‘n magdom inligting bevat rakende die kragte wat die versameling van molekules in die vaste fase beheer. Die siklotrifosfaseen afgeleides wat ‘n wye verskeidenheid substituente kan dra, kan hierdeur die moontlike intermolekulêre interaksies wat die versameling in die kristallyne vaste fase beheer verbreed. In hierdie studie is vyftien siklotrifosfaseen afgeleides gesintetiseer en gekarakteriseer. Die voorheen onbekende kristalstrukture van twee siklotrifosfaseen afgeleides is in hierdie studie geïdentifiseer, naamlik 2,2-bis(4-formielfenoksie)-4,4,6,6-bis[spiro(2',2"-dioksie-1',1"-bifeniliel)]siklotrifosfaseen en heksa(4-sianofenoksie)siklotrifosfaseen. Die strukture is bepaal deur enkelkristal X-straaldiffraksie. In die loop van hierdie studie is twee voorheen onbekende polimorfs van heksa(4-fluorofenoksie)siklotrifosfaseen geïdentifiseer en bestudeer. Die nuwe trikliniese vorm ondergaan ‘n onomkeerbare faseverandering na die monokliniese vorm by hoë temperature. Die bekende monokliniese P fase ondergaan egter ‘n verdere faseverandering na ‘n monokliniese C fase. Hierdie geskied as ‘n enkel-kristal na ‘n enkel-kristal faseverandering. Daar word ook gespekuleer dat hierdie spesifieke faseverandering wel omkeerbaar is indien die kristal na -45 °C afgekoel word. Een nuwe mede-kristal tussen heksa(4-pyridieloksie)sikotrifosfaseen en 1,3-dibensoësuur is in hierdie studie geïdentifiseer en gekarakteriseer. ‘n Analise van die Cambridge Strukturele Databasis het egter aangedui dat die vorming van mede-kristalle nie ‘n alledaagse verskynsel is in sikotrifosfaseen afgeleides nie. Dit lei tot die gevolgtrekking dat sikotrifosfaseen molekules wel in kristalingenieurswese gebruik kan word as supramolekulêre boustene, maar dat die vorm en grootte van die molekules die kristallisering van mede-kristalle verhoed. Dus moet die molekules wat saam met die siklotrifosfaseen molekules gekristalliseer wil word, goed deurdink word.

Thesis (MSc)--Stellenbosch University, 2012. / Please refer to full text for abstract

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2006. / Inclusion and porosity properties of the following supramolecular solid-state hosts were investigated: • 2,7-dimethylocta-3,5-diyne-2,7-diol • 2-methyl-6-phenylhexa-3,5-diyn-2-ol • Dianin’s compound • p-tert-butyl-calix[4]arene • 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxy-2,8,14,20- tetrathiacalix[4]arene • Two discrete coordination metallocycles, [Ag2IMID2](BF4)2 and [Cu2(BITMB)2(Cl)4] All of these compounds form well-defined crystalline host structures. Inclusion phenomena involving encapsulation of liquids were studied using single-crystal x-ray diffraction methods. Several guest-free host structures (α phases) were structurally elucidated and their gas sorption properties were investigated. Studies of the sorption properties of seemingly nonporous materials were carried out to provide insight into this rare phenomenon. Water and iodine sorption by a polymorph of 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxy-2,8,14,20- tetrathiacalix[4]arene shows that the conventional perception of sorption through the solid-state requires reassessment. Gas sorption studies were carried out using apparatus devised and presented here. These include sorption apparatus and a device to determine single-crystal structures under controlled gas atmospheres.

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2009. / Please refer to full text to view abstract.

Dissertation (PhD)--Stellenbosch University, 2004 / ENGLISH ABSTRACT: Over the past decade peptide bola-amphiphiles have been the subject of much attention because of their role as potential models of functionalised membranes and as new generation surfactants. In the quest for new surfactants a peptidomimetic-based approach was used to design a library of novel 'hybrid' bola-amphiphilic peptide surfactants derived from sapecin B and a model symmetrical oligo-glycine bola-amphiphile. The library was divided into different series, each one purpose-built; first, to investigate hierarchal supramolecular architecture and, second, to investigate potential antimicrobial activity. The bola-amphiphiles were synthesised using Fmoc-polyamide based solid phase peptide synthesis and purified via high performance liquid chromatography. The peptide hybrids were characterised using electro spray mass spectrometry, nuclear magnetic resonance, different modes of electron microscopy, Fourier-transform infrared spectroscopy and, in some cases, further studies were done using circular dichroism and bioactivity tests. The model bola-amphiphile suberamide(GGh was synthesised using peptide fragment condensation based on solid phase peptide synthesis. The synthesis is bi-directional (N~C and C~N) and versatile, making it possible to synthesis new dicarboxylic oligopeptide bola-amphiphiles and other analogous compounds. The product, suberarnide(GG)2, was purified using its inherent ability to self-assemble in an acidic solution. Novel asymmetrical bola-amphiphiles composed of dipeptide head groups linked via an aliphatic (I)-amino acid, serving as a hydrocarbon spacer, were also synthesized. Two small libraries of bola-amphiphiles were established - the first involved variation in to-amino acid length and the other variation in the C-terminal amino acid. The bolaamphiphiles were self-assembled in either 0.1% trif1uoroacetic acid or 0.1% triethylamine. Electron microscopy revealed the formation of a variety of higher order supramolecular architectures based on ~-sheet self-assembly. FT-IR spectrometry indicated that interlayer and intralayer hydrogen bond networks, together with strong selfassociation, promoted by the hydrophobic effect and, in certain instances, electrostatic interactions, are responsible for the variety of supramolecular architectures. Variations in the higher order structures can be attributed to amino acid composition, specifically length of m-amino acid, nature of the C-terminal amino acid and the optimised solvent conditions used for the self-assembly process. A third library of novel 'hybrid' bola-amphiphilic peptide surfactants, in which a cationic tripeptide motif from antimicrobial peptides was combined in a hybrid molecule containing a oi-amino acid residue, was established. These bola-amphiphiles displayed potent antimicrobial activity against both Gram-positive and Gram-negative bacteria; the analogues were as active or more active than the leader peptides yet, remarkably, displayed little or no appreciable haemolytic activity. These organopeptide bolaamphiphiles thus demonstrated selective toxicity towards bacteria. The hydrophobicity imparted by the co-amino acid has contrasting effects on haemolysis and antimicrobial activity of the peptide analogues. The other unique feature of these peptides and their analogues is the fact they self-assembled into complex supramolecular architectures, composed primarily of ~-sheets. Their self-assembly is primarily governed by hydrophobic interactions together with inter and intralayer hydrogen bonding. Electron microscopy clearly revealed higher order structures for both peptides and analogues. The generation of higher order supramolecular architecture is dependent on optimisation of ~- sheet self-assembly whereas antimicrobial activity is dependent on the balance between net positive charge and optimum hydrophobicity of the peptide hybrids. This study has demonstrated that it is possible to design hybrid peptide surfactants capable of producing higher order supramolecular architecture and improving the antimicrobial activity whilst reducing the haemolytic effect. The study and design of these versatile 'purpose-built' bio-inspired surfactants heralds a novel approach, one that shows tremendous potential. / AFRIKAANSE OPSOMMING: Die afgelope dekade het bola-amfifiliese peptiede baie aandag geniet weens hulle rolle as potensiële modelle van gefunksionaliseerde membrane en as 'n nuwe generasie surfaktante. In die soeke na nuwe surfaktante is 'n peptiedornimetiese benadering gevolg om 'n biblioteek van nuwe "hibried" bola-amfifiliese peptiedsurfaktante van sapesien B en 'n simmetriese oligoglisien bola-amfifil af te lei. Die biblioteek is in verskillende reekse onderverdeel. Elke reeks is doelmatig vervaardig om ondersoek in te stel na twee aspekte, nl. die rangorde van die supramolekulêre strukture en die potensiële antirnikrobiese aktiwiteit. Fmoc-poliamied gebaseerde soliedefase-peptied-sin-tese is aangewend vir die sintese van die bola-amfifile en hulle is met behulp van hoë doeltreffendheid vloeistofchromatografie gesuiwer. Die peptiedhibriede is gekarakteriseer met behulp van elekrosproei massaspektrometrie, kern-magnetiese resonansie, verskillende modusse elektronrnikroskopie, Fourier-transform infrarooispektrometrie en, in sommige gevalle is verdere studies met sirkulêre dichroïsme en bioaktiwiteitstoetsing uitgevoer. Die bola-amfifilsuberamiedtflfij--model is met behulp van peptiedfragment-konden-sasie gesintetiseer gegrond op soliedefase-peptiedsintese. Dit sintese vind in twee rigtings plaas (N~C en C~N) en is veelsydig aangesien dit die sintese van sowel nuwe dikar-boksielbola- amfifile as ander analoë verbindings moontlik maak. Die produk, suber-arnied(GG)2, is gesuiwer met behulp van die verbinding se inherente vermoë tot self-montering in suur oplossings. Nuwe assimetriese bola-amfifile, saamgestel uit dipeptiedkopgroepe, gekoppel via 'n alifatiese ro-aminosuur, wat as koolwaterstofspasieerder dien, is ook gesintetiseer. Twee klein bola-amfifilbiblioteke is saamgestel - die een het variasies in die ro-aminosuur se lengte omvat en die ander een variasies in die C-terrninale aminosuur. Selfmontering van die bola-amfifile het plaasgevind in of 0,1 % trifluorasynsuur Of 0,1 % trietielamien. Elektronrnikroskopie het die bestaan van 'n verskeidenheid hoërorde supramolekulêre strukture, gegrond op p-plaatselfmontering, aangetoon. Uit FT-IR-spektrometrie blyk dit dat inter - en intralaag waterstofbinbdingsnetwerke en sterk selfassosiasie, 19. word bevorder deur die hidrofobiese effek en, in sekere gevalle, elektrostatiese interaksies, is verantwoordelik vir die verskeidenheid supramolekulêre strukture. Variasies in die hoërorde strukture kan toegeskryf word aan aminosuursamestelling, in besonder die lengte van die ro-aminosuur, die aard van die C-terminale aminosuur en die geoptimiseerde oplosmiddelkondisies wat gebruik is vir die selfmonteringsproses. 'n Derde biblioteek nuwe "hibried" bola-amfifiliese peptiedsurfaktante, waarin 'n kationiese tripeptiedmotief uit antimikrobiale peptiede gekombineer is met 'n m-aminosuurresidu, is geskep. Sommige van hierdie bola-amfifile het 'n kragtige antimikrobiese aktiwiteit teenoor sowel Gram-positiewe as Gram-negatiewe bakterieë gertoon. Die analoë strukture was aktief, of selfs meer aktief as die voorste peptiede maar het, verbasend genoeg, nie 'n beduidende hemolitiese aktiwiteit vertoon nie. Hierdie organopeptied bola-amfifil het dus 'n selektiewe toksisiteit teenoor bakterieë vertoon. Die hidrofo-bisiteit, as gevolg van die ui-aminosuur, het 'n resiproke effek op hemolise en die antimikrobiese aktiwiteit van die peptiedanaloë. Die ander uitstaande kenmerk van die peptiede en hulle analoë is die vermoë om te selfmonteer en komplekse supramolekulêre strukture, bestaande hoofsaaklik uit ~-plate, te vorm. Hierdie selfmontering word in hoofsaak beheer deur hidrofobiese interaksies asook inter - en intralaagwaterstofbinding. Elektronmikroskopie het duidelik hoërorde strukture getoon by sowel dié peptiede as hulle analoë. Die ontwikkeling van hoërorde supramolekulêre struktuurvorms is afhanklik van die optimalisering van die ~-plaatselfmontering. Daarteenoor is die antimikro-biese aktiwiteit afhanklik van die balans tussen die netto positiewe lading en die opti-male hidrofobisiteit van die peptiedhibriede. Hierdie studie het getoon dat dit moontlik is om hibriedsurfaktante te ontwerp wat hoërorde supramolekulêre strukture te produseer en om die antimikrobiese aktiwiteit te verbeter terwyl die hemolitiese effek verminder word. Die studie en ontwerp van hier-die veeldoelige, "doelmatig-gesintetiseerde" biogeïnspireerde surfakante stel 'n unieke benadering daar, wat oor groot potensiaal beskik.

Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: A theoretical and experimental study was performed in order to identify factors that influence the propensity of compounds containing anionic functional groups that are commonly found on pharmaceutical drug compounds to form hydrates. A Cambridge Structural Database (CSD) survey was initially undertaken to determine the propensity of different pharmaceutically acceptable anions to form hydrates. The results showed that hydrate formation will take place more regularly when the polarity of the functional group increases. Furthermore, if the charge distribution is very concentrated over the polar groups, hydrate formation will occur more readily. This observation was further investigated by performing a series of potential energy surface (PES) scans for the hydrogen bond (H-bond) in the structure of N-(aminoiminomethyl)-N-methylglycine monohydrate (creatine monohydrate) with various Density Functional Theory (DFT) and Wave Functional Theory (WFT) methods. WFT is often also referred to as ab initio, which refers to the construction of the wave function from first principles when this theory is applied. The scans revealed that several strong and directional H-bonds with different geometrical parameters between the carboxylate group and the water molecule are possible, which suggests that the H-bond plays an important role in driving the formation of pharmaceutical hydrates. A total of 44 hydrate structures were identified that have pharmaceutically acceptable functional groups. Optimisations in the gas phase and in an implicit solvent polarisable continuum solvent model with a variety of solvents showed that there is a significant dependence of the H-bond interaction energy on the anionic group as well as the steric density of surrounding substituents. It was found that the M06-2X method utilising the 6-311++G(d,p) basis set outperformed the other methods that were tested when compared to optimisations performed with the benchmark MP2/aug-cc-pVTZ level of theory. Furthermore, the strength of the H-bond was measured in the 44 experimentally determined structures by using a total of five generalized gradient approximation (GGA) methods, of which two methods contained the DFT-D3 correction. The results of these DFT methods were subsequently compared to results obtained at the benchmark MP2/aug-cc-pVTZ level of theory. The M06-2X method was identified as the most economical method to calculate H-bond energies. It was also found that the H-bond interaction energy shows a substantial dependence on the electrostatic environment. This was observed by a significant decrease in H-bond strength as the relative permittivity of the solvent increases. The effect of steric density on the H-bond interaction energy was investigated by performing hydrogen bond propensity calculations. These values were then compared to the interaction energies of each structure and the results showed that the presence of large bulky substituents can lead to an increase in bond energy by forcing the anionic functional group closer to the water molecule. Contrastingly, the bulky group can also push the anionic group away from the water molecule and result in a decrease in bond energy. Approximate values for the amount of stabilisation offered to the H-bonding system by the surrounding crystalline environment were calculated by optimising the H-bond geometrical parameters of selected compounds with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. The H-bond interaction energies were then calculated at the M06-2X/6-311++G(d,p) level of theory and compared to the H-bond interaction energies in geometries that have been fully optimised. After these energies were compared and the crystal packing of each structure was investigated, it was found that the packing of some structures within the crystalline environment limits the number of H-bonds that can be formed between the water and the compound of interest. Full optimisation calculations result in structures with cooperative stabilisation, such that more than one H-bond is found between the two fragments. The effect of substituents on H-bond interaction energy was investigated by the addition of six electron-donating and electron-withdrawing groups on four aromatic compounds with different anionic functional groups, namely carboxylate, nitrogen dioxide, sulfonate and phosphonate. It should also be mentioned that the nitrogen dioxide is not an anionic functional group, but it was included as it is a neutral radical that often forms hydrogen bonds. A total of 80 structures were optimised with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. This was followed by counterpoise corrected single point calculations at the M06-2X/6-311++G(d,p) level of theory. The results showed that the H-bond interaction energy bears no relationship to the inductive strength or the inductive ability of the substituents, but rather the ability of these substituents to rotate the anionic functional group and allow cooperative stabilisation of the H-bond. Furthermore, AIM analysis was performed for the substituted H-bonded aromatic structure. The results showed that electron-donating groups that are placed at the para position yield stronger H-bonds, which is once again accompanied by cooperative stabilisation. Electron-withdrawing groups with sufficient inductive effects can result in a weaker H-bond when placed at the meta position. The effect of water activity (aw) on the hydrate crystal formation was investigated experimentally by performing a series of crystallisations in various solvent mixtures. These mixtures consisted of water mixed with acetone, ethanol and ethyl acetate. A total of three organic acids were used in crystal formation, namely pyridine-4-carboxylic acid (isonicotinic acid), N-amino-iminomethyl-N-methylglycine (creatine) and benzene-1,3,5-tricarboxylic acid. It was found that water activity affects the formation of the hydrate as well as the anhydrous product. Additionally, nucleation and super saturation plays a large role in crystal formation and can serve as an effective technique when the formation of crystals of an appropriate shape and size is required for further analysis. / AFRIKAANSE OPSOMMING: 'n Teoretiese en eksperimentele studie was uitgevoer om faktore te identifiseer wat die geneigdheid van verbindings met anioniese funksionele groepe wat algemeen gevind word op farmaseutiese dwelm verbindings om die hidraat produk te vorm, affekteer. 'n Opname van strukture in die Cambridge Strukturele Databasis (CSD) is onderneem om die geneigdheid van verskillende farmaseutiese aanvaarbare anione om hidrate te vorm te bepaal. Die resultate het getoon dat hidraatvorming meer gereeld plaasvind indien die polariteit van die funksionele groepe toeneem. Verder is daar ook opgemerk dat 'n gekonsentreerde ladingsverspreiding op die polêre groepe ook tot 'n toename in hidraat vorming sal lei. Hierdie waarneming is verder ondersoek deur 'n reeks potensiële energie oppervlak (PES) skanderings van die waterstof binding (H-binding) vir die struktuur van N-amino-iminometiel-N-metielglisien monohidraat (kreatien monohidraat) met verskeie Digtheids-Funksionele Teorie (DFT) en Golffunksie Teorie (WFT) metodes uit te voer. Die skanderings het getoon dat verskeie sterk, gerigte H-bindings met verskillende geometriese parameters tussen die karboksilaatgroep en die watermolekule kan vorm. Hierdie bevindinge lê klem op die belangrike rol wat H-bindings in die vorming van farmaseutiese koolhidrate speel. 'n Totaal van 44 hidraat strukture met farmaseutiese aanvaarbare funksionele groepe was geïdentifiseer. Optimaliserings is in die gas fase asook in 'n implisiete kontinuum polariseerbare oplosmiddel model met 'n verskeidenheid oplosmiddels uitgevoer. Die resultate het 'n beduidende afhanklikheid van die H-binding interaksie-energie op die anioniese groep asook die steriese afkskerming van omringende groepe getoon. Daar is bepaal dat die M06-2X metode wat saam met die 6-311++G(d,p) basisstel die mees akkuraatste resultate gelewer het in vergelyking met die ander DFT metodes asook die MP2/aug-cc-pVTZ maatstaf. Die H-binding se sterkte is vir hierdie strukture bereken deur vyf GGA metodes te gebruik, waarvan twee metodes van die DFT-D3 korreksie gebruik maak. Die resultate van die berekeninge met hierdie DFT metodes is daarna vergelyk met resultate verkry met die MP2/aug-cc-pVTZ maatstaf. Daar is gevolglik bepaal dat die M06-2X metode die mees ekonomiese metode is om H-binding energië te bereken. Die H-binding interaksie energie toon 'n aansienlike afhanklikheid op die diëlektriese konstante van die oplosmiddel aan. Hierdie waarneming is op grond van 'n beduidende afname in die H-binding interaksie-energie indien die relatiewe permittiwiteit van die oplosmiddel verhoog word gemaak. Die effek van steriese digtheid is ondersoek deur waterstofbindinggeneigdheid waardes te bereken. Hierdie waardes is met die interaksie-energië van elke struktuur vergelyk. Die resultate dui daarop dat steries digte groepe tot 'n toename in interaksie energie kan lei wanneer die anioniese funksionele groep nader aan die water molekule gestoot word. Verder is dit ook moontlik vir hierdie steries digte groepe om die anioniese groep weg van die water molekule te stoot en gevolglik 'n afname in interaksie energie te veroorsaak. Benaderde waardes vir die hoeveelheid stabilisering wat die omringende kristallyne omgewing aan die H-binding bied is bereken deur die H-binding geometriese parameters van geselekteerde verbindings met die M06-2X en MP2 metodes en die 6-311++G (d,p) basisstel te optimaliseer. Die H-binding interaksie-energië is gevolglik by die M06-2X/6-311++G(d,p) vlak van teorie bereken en met die H-binding energië in strukture wat volledige optimaliseer is vergelyk. Nadat hierdie waardes vergelyk is, is daar gevind dat die pakking van strukture in the kristallyne omgewing verhoed dat sekere H-bindings tussen die water molekule en die verbinding van belang kan vorm. Strukture wat volledig optimaliseer is, lei tot strukture wat in staat is om koöperatiewe stabilisering te ondergaan. Koöperatiewe stabilisering word gekenmerk deur die vorming van meer as een H-binding tussen twee fragmente. Die effek van substituente op die H-binding interaksie energie is ondersoek deur die bevoeging van ses elektrondonor- en elektronontrekkendegroepe op vier aromatiese verbindings, naamlike die karboksilaatgroep , stikstofdioksied , sulfonaat en fosfonaat. Dit moet ook genoem word dat stikstofdioksied nie 'n anioniese funksionele groep is nie, maar dit was wel ingesluit omdat dit ‘n neutrale radikaal groep is wat dikwels waterstofbindings vorm. 'n Totaal van 80 strukture optimiserings was uitgevoer met 'n kombinasie van die M06-2X en MP2 metodes wat gebruik maak van die 6-311++G(d,p) basisstel. Dit is gevolg deur interaksie-energie berekeninge op die M06-2X/6-311++G(d,p) vlak van teorie. Die resultate het getoon dat daar geen verband tussen die induktiewe vermoë van die substituente en die sterkte van die H-binding is nie, dit is eerder die vermoë van hierdie substituente om die anioniese funksionele groep te laat roteer wat toelaat dat koöperatiewe stabilisering van die H-binding kan geskied. Die AIM analise is op 'n gesubstitueerde H-binding struktuur toegepas. Die resultate het getoon dat elektrondonorgroepe wat by die para posisie geplaas word tot sterker H-bindings sal lei, wat weereens met koöperatiewe stabilisering vergesel word. Elektrononttrekkendegroepe met sterk induktiewe effekte kan tot 'n swakker H-binding lei indien hulle by die meta posisie geplaas word. Die effek van water aktiwiteit (𝑎w) op hidraatkristalvorming is deur die uitvoering van 'n reeks kristallisasies in verskeie oplosmiddelmengsels ondersoek. Hierdie oplosmiddel mengsels bestaan uit water met asetoon, etanol of etielasetaat gemeng. Kristallisasies is vir drie organiese sure, naamlik piridien-4-karboksielsuur, N-amino-iminometiel-N-metielglisien monohidraat en 1,3,5-benseen tri-karboksielsuur uitgevoer. Daar is gevind dat water aktiwiteit 'n invloed op die vorming van die hidraat en watervrye produkte kan hê. Daarbenewens, speel water aktiwiteit 'n belangrike rol in die nukleasie fase van kristalvorming en kan as 'n effektiewe tegniek dien om kristalle van 'n toepaslike vorm en grootte vir verdere analise te verkry.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy