Using confocal Raman spectroscopy/microscopy, we have monitored pharmaceutical crystallisation 'in situ' in three model (well characterised polymorphic systems) Active Pharmaceutical Ingredients (APIs) and one previously unstudied system where polymorphism had not being reported prior to this study: flufenamic acid, a Non Steroidal Non-Inflammatory Drug (NSAID); nifedipine, an antihypertensive; tolbutamide, used in the treatment of type II diabetes; and imipramine hydrochloride, an antidepressant respectively. Constrained crystallisation from the solid amorphous state was utilised to kinetically trap polymorphs via the Ostwald's rule of stages. Particular emphasis was placed on the phonon-mode/low wavenumber region (4-400cm-1) of the Raman spectral window (this region provides useful information about lattice environment). In all cases our results from the Raman experiments were complemented with similar experiments using Differential Scanning Calorimetry (DSC) and Variable Temperature X-ray Powder Diffraction (VTXRPD). To reduce data complexity, principal component analysis was deployed and found to be extremely effective. In chapter two, a multi-technique study of flufenamic acid (FFA) was carried out which served as a groundwork for later chapters. A solid-solid transformation between two forms of FFA (forms I and III) was observed, due to the abrupt nature of this transition, the 'Lindemann vibrational catastrophe' was envisaged as a possible mechanism for the transformation. Using FFA as a test case in chapter three, polymorphic transformations was monitored in both FFA forms I and III using in situ Raman spectroscopy (as well as VTXRPD) by adopting the constrained crystallisation approach. The approach showed excellent promise (with the XRPD patterns of FFA form II and one unknown form uncovered) and was further explored in later chapters using a variety of pharmaceutical materials. While in chapter four, the interconversion between the different polymorphs of nifedipine was studied using the constrained crystallisation approach monitored using in situ Raman spectroscopy (together with VTXRPD and DSC), our results compared favourably well with those previously published in literature. We also reported for the first time the phonon-mode Raman spectral for this system as earlier publications focussed only on the 'traditional' fingerprint region. Similarly in chapter five, in situ Raman spectroscopy was also used to monitor the polymorphic transformations in tolbutamide (using the constrained crystallisation approach), results from the Raman analysis was compared with those obtained from VTXRPD and found to be in agreement. Thus further showing that Raman spectroscopy combined with the constrained crystallisation approach is a veritable tool for monitoring polymorphic transitions. In chapter six, preliminary results (Raman/XRPD/DSC) showed for the first time that imipramine hydrochloride exhibits polymorphism, with the possibility of at least two new polymorphs. Combination of state of the art spectroscopic techniques with appropriate statistical methods, X-ray powder diffraction and DSC was shown to be an extremely effective approach to investigating and characterising polymorphism in drugs, often using only milligram or sub-milligram sample quantities. Lastly in chapter seven, the novel technique of Transmission Raman Spectroscopy (TRS) was employed in carrying out a quantitative study of polymorphic content in a model pharmaceutical formulation and the results obtained compared with those from traditional backscattering geometry. The transmission method is shown to provide a true bulk measurement of the composition, being unaffected by systematic or stochastic sub-sampling issues that can plague traditional backscattering geometries.

The crystallization of molecules from solution encompasses a number of key areas in science and technology, ranging from the purification and separation of industrial chemicals through to the arrangement of fragile biomacromolecules in ordered arrays suitable for structural analysis. However, as there are only a small number of techniques suitable for the study of such assemblies, many fundamental aspects governing the crystallization of molecules from solution are still poorly understood. In the studies presented here we have attempted to improve the understanding of this subject by investigating the crystallization of a series of molecules of both pharmaceutical and biological importance, using in situ Atomic Force Microscopy (AFM). A particular aim of the PhD was to develop the experimental protocols necessary to investigate macromolecular crystals known to exhibit poor diffraction properties, and subsequently to relate AFM data to these properties. The first study carried out concerned the crystallization and habit modification of a pharmaceutical excipient molecule, adipic acid. By using AFM we were able, for the first time, to directly observe the behavior of the dominant (100) face in both an air and liquid environment. A number of important observations were made including solute reorganization in air, etch pit formation and growth inhibition by the structurally related habit modifier, octanoic acid. We subsequently investigated various aspects of the crystallization of the model protein, lysozyme. The rate and mechanisms of growth of the (110) surface of the tetragonal crystal were observed using in situ AFM at a range of supersaturations, a study that uncovered a previously unreported mechanistic event. The (110) and (101) faces were then both investigated at higher resolution, revealing molecular resolution features corresponding directly to basic crystallographic data. The polymorphic characteristics displayed by many macromolecular crystals were then investigated in a short study concerning the growth and structure of the monoclinic form of the lysozyme crystal. The dominant (101) face of the crystal was investigated at both high and low protein/precipitant concentrations, allowing us to unambiguously distinguish between two crystalline forms of the same macromolecule. Finally, by utilizing the experimental techniques developed throughout the previous studies, we investigated a poorly diffracting crystal constructed from a protein found in Streptococcus pneumoniae, Response Regulator 02 receiver domain (RR02rec). By studying the surface of crystalline RR02rec with in situ AFM, we were able to uncover various features of the crystal lattice that may have contributed to the poor diffraction properties displayed by the crystal during previous X-ray studies. Besides revealing a range of new molecular scale details concerning the structure and growth of each of these crystal systems, these studies culminated in a successful attempt to relate direct microscopical observations of growth dynamics of a protein crystal system (RR02rec) to the limited results obtained from previous crystallographic studies performed on this protein. As an approach this offers considerable promise in identifying problems with certain crystals and, in conjunction with future advances in AFM technology, may offer information that could lead to the acceleration and enhancement of X-ray diffraction analyses.

The importance of crystals to the pharmaceutical industry is evident - over 90% of pharmaceutical products contain a drug in crystalline form. However, the crystallization phenomena of drug compounds are poorly understood. An increased understanding of these processes may allow a greater degree of control over the crystallization outcomes, such as morphology, purity, or stability. In these studies, we have applied Atomic Force Microscopy (AFM) to the in situ investigations of drug crystal growth. We utilized AFM to assess the growth on the (001) face of aspirin crystals at two supersaturations, elucidating both the growth mechanisms and kinetics at each supersaturation. We also investigated the nucleation of aspirin crystals, using microcontact printing to arrange aspirin-binding and non-binding self-assembled monolayers (SAMs) onto surfaces. This facilitated the visualization, using AFM, of the growth of aspirin crystals adhered to the surface. Additionally, secondary nucleation was observed on the growing crystals. The effect of the additives acetanilide and metacetamol on the morphology and growth on the (001) face of paracetamol was investigated. The presence of metacetamol significantly reduced the growth rate on the face, with respect to pure paracetamol solutions. The growing steps exhibited a pinned appearance, consistent with the Cabrera and Vermilyea model. Conversely, acetanilide caused dissolution to occur. Finally, we assessed the capabilities of AFM in following the structural transformations of crystals, which can occur in unstable pharmaceutical compounds. We employed AFM to determine the process by which anion exchange, and the subsequent structural transformations, of the co-ordination polymers {[Ag(4,4'-bipy)]BF4} and {[Ag(4,4'-bipy)]NO3} occur. AFM data verified that the anion exchange process is solvent-mediated. The mechanisms underlying this process are discussed herein. These results reiterate the capability of AFM to monitor dynamic events on crystal surfaces. Analogous studies could be applied to numerous pharmaceutical compounds, thus facilitating the optimization of their crystallization parameters. In essence, future experiments using AFM may afford greater control over crystallization, and prevent the production of unwanted or unstable pharmaceutical compounds.

Novel polycatenar bent-core Schiff-base metallomesogens from derivatives of 1,1 O-phenanthroline ([MCb(LPhen-n)]), 2,2-bipyridine ([MCb(L Bipy-n)]) and 5,5'-dimethyldipyrromethane ((tc)_[M(LDipy-n)] and ex-[M(L Dipy-n)]) have been investigated in this body of work. The mesomorphic properties of these first- and second-row transition metal complexes have been studied. Further to the examination of the compounds in the liquid crystalline state, single crystal X-ray studies of short chain analogues were performed to determine the coordination geometry and the degree of selfassembly of the molecules in the solid state. Chapter 1 introduces the field of liquid crystals and metallomesogens, with a focus on thermotropic liquid crystals and their nomenclature, physical properties and applications. The historical background of the field is briefly explored and previous research on bent-core metallomesogens from the Schroder group in Nottingham has been reviewed. The characterisation of liquid crystalline mesophases, namely by polarised optical microscopy, differential scanning calorimetry and X-ray diffraction, are described. Further discussion is dedicated to the X-ray diffraction patterns generated by columnar mesophases. The chapter finishes with a description of the aims of the project. Chapter 2 commences with an introduction to liquid crystals derived from 1,1 O-phenanthroline. Following this is a description of the synthesis and characterisation of mesomorphic metal-free ligands, LPhen-n (n = 10, 12, 14, 16), four novel series of metallomesogens and two non-mesomorphic series of complexes derived from 1,10-phenanthroline, [MCb(LPhen-n)] (M = Mn2+, Fe2~, C02+, Ni2+, Cu2+. Zn2+~ LPhen = 2.9-bis-[3' A ',5' -tri(alkoxy)phenyliminon1ethyl]- 1,1 O-phenanthroline: n = 8, 10, 12, 14, 16). Structural determination by single crystal X-ray diffraction of the analogous methoxy complexes [MCb(LPhen-l)] (M = Mn2+, C02+, Ni2+, Zn2+), and the complex without any lateral aliphatic groups [CuCb(LPhen-O)], revealed the metal (II) complexes to have either distorted trigonal bipyramidal, square pyramidal or octahedral coordination geometry. The mesomorphic behaviour of the complexes [MCb(LPhen-n)] (M = Mn2+, C02+, Ni2+, Zn2+; n = 8, 10, 12, 14, 16) and the metal-free ligands LPhen-n (n = 10, 12, 14, 16) is columnar (with the exception of the non-mesomorphic [CoCb(LPhen-8)]), and the 2D symmetries of these mesophases vary between hexagonal, rectangular and oblique. Chapter 3 is introduced with a discussion of liquid crystalline compounds derived from 2,2' -bipyridine. Subsequently, the synthesis and characterisation of four new series of metallomesogens and two nonmesomorphic compounds derived from 2,2' -bipyridine, [MCb(L Bipy-n)] (M = Mn2+, Fe2+, C02+ Cu2+ and n = 16; M = Ni2+, Zn2+ and n = 10, 12, 14, 16; L Bipy = 6,6' -bis-[3' ,4',5' -tri(alkoxy)phenyliminomethyl]-2,2' -bipyridine) are detailed. Single crystal X-ray diffractometry revealed the coordination geometry• of [MnCb(LBipy-l)], [CoCb(LBipY-l)] and [NiCb(LBipy-l)] to be octahedral, whereas [ZnCb(LBipY-l)] is distorted trigonal bipyramidal. The complexes [MCb(L Bipy-n)] (M = Mn2+, C02+ and n = 16; M = Ni2+, Zn2+ and n = 10, 12, 14, 16) exhibit mesomorphic character and again generate columnar mesophases. Finally, Chapter 4 begins with a discussion on pyrrole-derived liquid crystals. Consequently, the synthesis and characterisation of hexacatenar d compoun s [M(LDipH/)] \: (M -- 2H ,Zn 2+, Pd2+.' n = 10 ,_l', 1'1"t o 16', x. = 1, ,-), tetracatenar compounds tc_[M(LDip~-16)1\ (M = 2H, Zn2+, Pd2T ; x = 1, 2) and extended dicatenar compounds ex_[M(LDipy-n)]x (M = 2H, Zn2+, Pd2+; x = 1. 2) are described. Characterisation by X-ray diffraction of single crystals of [Zn(LDipy-l)h, ex-[Zn(LDipy-l)h show they exhibit a distorted tetrahedral geometry, forming double stranded helical structures, while ex-[Pd(L Dipyl)] has a distorted square planar geometry. The metal-free ligands H2LDip~-1/ (n = 10, 12, 14, 16) and complexes [Zn(LDipy-16)h and [Pd(LDipy-n)] (n = 12, 14, 16) all exhibit narrow mesomorphic temperature ranges and unidentified mesophases. The tetracatenar compound tc_[Zn(LDipy-16)h generates a columnar hexagonal mesophase and the complex tc_[Pd(LDipy-16)] generates an unidentified liquid crystalline phase, whereas the metal-free ligand tc-H2L Dipy-16 has no mesomorphic character. Finally, two of the extended dicatenar compounds ex-H 2L DipY-16 and ex-[Zn(L Dipy-16)h are non-mesomorphic, while ex-[Pd(L Dipy-16)] was found to have a smectic A phase.

Co-crystals are multi-component, single phase materials in which the co-crystal formers exist in an uncharged state. This interaction between components occurs without affecting the intra-molecular covalent bonding of the involved components or altering their chemical integrity. This class of materials has recently gained the interest in the pharmaceutical industry for modifying the physico-chemical properties of some active pharmaceutical ingredients (APIs) such as solubility, hygroscopicity, and mechanical properties. However like all multi-component systems, there are some analytical challenges associated with using traditional quality control (QC) tools that involve sample preparation steps prior to the analysis. This can sometimes have an impact on the physical state of such systems and therefore affect the outcomes of analysis correlated with the actual materials. Flurbiprofen (FBP) and nicotinamide (NCT) in this work were selected to form a model co-crystal system. FBP falls in the carboxylated group of non steroidal anti-inflammatory drugs (NSAIDs), used herein as an API. It belongs to class II of the Biopharmaceutics Classification System (BCS), therefore its low aqueous solubility and dissolution rate affect its bioavailability. NCT is a vitamin B3 derivative and generally regarded as safe (GRAS) substance. It is used as co-crystallising agent due to its solubility enhancing property. FBP-NCT co-crystal system was previously studied by Berry et al., where a FBP-NCT co-crystal was prepared using Kofler method and screened by means of the hot-stage microscopy (HSM). FBP-NCT co-crystal was recently prepared via rapid evaporation from ethanol solution, and screened for its physicochemical and mechanical properties by Shing et al. who found an improvement in such properties compared to the pure API (FBP). There is a wide range of methods for preparing co-crystals, of which methodologies with minimal environment impact were mainly adopted in this work i.e., Ko er fusion and co-grinding methods. Within the Kofler fusion method, it was feasible to identify and screen simultaneously parent components as well as the emerging material at room temperature (RT) by means of confocal Raman microscopy. Detailed information from Raman mapping on the investigated phases were achieved using statistical analysis. The analysis resulted in a refinement regarding the traditional assumption about the binary phase diagram. It also revealed the presence of two forms of FBP-NCT co-crystals which were consequently explored by coupling thermal analysis with Raman spectroscopy and X-ray diffraction. Using co-grinding preparation, FBP-NCT co-crystals were prepared on a large scale; enough for solid dosage formulation. Subsequent crystallisation of the resulting compound using a solution method generated single crystals suitable for x-ray crystal structure determination. Moreover in this work, a solid-state dosage form of FBP-NCT co-crystal was prepared for the first time, then investigated using transmission Raman spectroscopy. The investigation included the presence of drug and excipient, and their composition in tablets. This procedure can be considered as a platform for studying the QC of drug preparation, using a reliable, non-destructive, non-invasive, and very rapid analytical tool. Such type of study complied well with the food and drug administrative (FDA) outlines on employing process analytical technology (PAT) protocol for analysing and controlling pharmaceutical manufacturing processes.

Chapter 1: An introduction is given to high-pressure crystallography with the experimental design and equipment required outlined. The basic theory that underpins X-ray diffraction and structure solution is covered with emphasis given to points that raise considerations for high-pressure crystallographic studies; key software and their uses are briefly introduced. A literature survey of molecular coordination complexes under pressure is given that provides a detailed view of the typical phenomena observed and interrogated in such work. Chapter 2: Recrystallisation of [PdCl2([9]aneS2O)] ([9]aneS2O = 1-oxa-4,7-dithiacyclononane), 1, and [PtCl2([9]aneS2O)], 2, by diffusion of Et2O vapour into solutions of these complexes in CH3NO2 has yielded three phases of 1 and two phases of 2. The phase of 1, herein designated α-1, was obtained under ambient conditions. A second phase, designated β-1, was initially also obtained by this method; following the advent of a third phase, γ-1, all subsequent efforts over a period of a year to crystallise β-1 yielded either γ-1, which was typically obtained by carrying out the recrystallisation at elevated temperature, or α-1, commonly found throughout the study. This persistent absence of a phase which could initially be crystallised with ease led to the conclusion that β-1 was an example of a ‘disappearing polymorph’. The first phase obtained of 2, designated α-2, was obtained by recrystallisation under ambient conditions and is isomorphous and isostructural with α-1. The second phase, β-2, was obtained by slight elevation of the recrystallisation temperature and was found to be isomorphous and isostructural with β-1. Subsequently, β-2 was used to seed the growth of the disappearing polymorph β-1. No third phase of 2 ("γ-2") has been isolated. Density functional theory calculations were employed to aid in rationalising this behaviour. Chapter 3: The three reported phases of the mononuclear macrocyclic Pd(II) complex [PdCl2([9]aneS2O)] (1) were each studied up to pressures exceeding 90 kbar using high pressure single crystal X-ray diffraction. The α and γ phases both exhibited smooth compression of the unit cell parameters with third-order Birch-Murnaghan bulk moduli of 14.4(8) and 7.6(6) GPa, respectively. Between 68.1 and 68.7 kbar β-1 was found to undergo a reversible transformation to a phase denoted β’ and characterised by a tripling of the unit cell volume. Across the phase transition, rearrangement of the conformation of the bound macrocycle at two of the resulting three unique sites gave rise to an extensively disordered structure. This phenomenon was largely owed to a close and approximately linear C−H···H−C approach between macrocycles. Density functional theory calculations were employed to further understand the high-pressure behaviour of the phases. Cooling from 290 to 90 K in complementary variable temperature crystallographic studies revealed similar effects as ca. 5 kbar pressure. Chapter 4: The two reported phases of the mononuclear macrocyclic Pt(II) complex [PtCl2([9]aneS2O)] (2) were each studied up to pressures exceeding 90 kbar using high pressure single crystal X-ray diffraction. The α phase exhibited smooth compression of the unit cell parameters with third-order Birch-Murnaghan bulk modulus of 11.8(5) GPa. Between 65.2 and 69.9 kbar β-2 was found to undergo an incomplete rearrangement of the macrocycle that was not characterised by a phase transition as seen for the corresponding Pd(II) phase. The β phase was also indicated to be more resistant to compression than the α phase with a third-order Birch-Murnaghan bulk modulus of 13.5(5) GPa. The conformational rearrangement was again rationalised by a close and approximately linear C−H···H−C approach between macrocycles. Density functional theory calculations were employed to further understand the high-pressure behaviour of these two phases and why β-1 and β-2 might differ. Cooling from 290 to 90 K in complementary variable temperature crystallographic studies again revealed similar effects as ca. 5 kbar pressure. Chapter 5: The previously unreported solvate [Pd([9]aneS3)2](PF6)2·2CH3NO2 is studied using high-pressure crystallography, high-pressure solid-state UV/vis spectroscopy and density function theory calculations to interrogate the piezochromism previously observed by this group. Up to 49.3 kbar, gradual sky blue to dull green piezochromism was observed with considerable compression of the elongated axial Pd···S interactions. A reversible P21/c → P-1 phase transition with doubling of the unit cell volume was observed between 49.3 and 51.0 kbar. This was accompanied by a dull green to orange stepwise piezochromism and characterised by an organised reorientation of the coordination axes in 50 % of the cations. The phase transition had a range of effects on the axial interactions which remained compressible in the high-pressure phase. No further piezochromism was clearly observed. Density functional theory calculations showed a fair match with experimentally obtained spectra and strongly indicated that the piezochromism is primarily owed to compression of the axial interaction. These calculations also indicated that outer-sphere effects further modulate the piezochromism, but gave no evidence for a cause of the phase transition. The phase transition was thus rationalised as a response to the large value of the PV term of the Gibb’s free energy associated with the transition. The ambient pressure structures of two other previously unreported solvates are also reported. Chapter 6: The templated polyiodide framework [Ag([18]aneS6)]I7 were studied to ca. 45 kbar. Each of the two crystals employed in this study underwent two phase transitions: at ca. 11 kbar an R-3m → R3m transition was observed in both crystals. This appeared to be ferroelectric in nature and was associated with a change in bonding of the polyiodide network from 3∞[I−·(I2)6/2] to 3∞[I7−]. Analysis of the calculated Mayer bond orders for the catenating I−···I2 interactions supported this description of the bonding. Compression of the first phase appears essentially the same for both crystals; compression through the second phase differed between crystals and the second phase transition, at ca. 40 kbar in both cases, resulted in differing monoclinic phases. The second transition was associated with the ordering of the conformation of the macrocycle: one phase appeared ordered from the perspective of the refinement and the macrocycle adopted the previously unseen [84114] conformation by Dale analysis. The other phase appears disordered from the perspective of the refinement but would appear to comprise alternating enantiomers of the [333333] conformer. The differing conformation of the macrocycle in the third phase was taken as indicative of differing major components in the disordered lower phases. This point of difference in turn rationalised the different response to pressure in the second phase: compression of the second phase is limited by interactions between cations while the first phase is dependent on the catenating I−···I2 interactions which are identical between crystals. Chapter 7: A summary of the key findings of this body of work is given along with suggested avenues for future studies. This thesis closes with the wider reaching considerations that are highlighted by this body of work.

A series of salts of the radical ion TCNQ were prepared by standard organic techniques or by controlled electrocrystallisation and their three-dimensional crystal structures were determined by single crystal X-ray diffractometry. The crystallisation of the two-phase system found in 1,2-bis(1-ethyl-4-pyridinio)ethene (TCNQ)4 was studied using a.c. conductivity techniques. The results showed phase formation to be dependent upon both concentration and cooling rate, and no evidence was found for a third phase possessing a metallic d.c. solid state conductivity. The structures reported in detail are: a) 1,4-dimethylpyridinium (TCNQ)2' DMPY(TCNQ)2' Triclinic, a = 7.833, b = 13.889, c -7.171Angstrem, alpha = 106.81, beta = 112.50, gamma = 95.36°, z = 1, space group P1. TCNQ moieties stacked as discrete diads with an interplanar separation of 3.21 Angstrem within the diad. The d.c. dark conductivity was measured (sigma 300 = 1.7 x 10 (-4) ohm cm (-1)) and is consistent with the observed structure. b) 2,3-bis(1-methyl-4-pyridinio)butane (TCNQ)4' DMPB (TCNQ)4, Triclinic, a = 7.798, b = 14.248, c = 13.690 Angstrem, alpha = 109.53, beta = 103.37, gamma = 95.42°, Z = 1, space group P1. TCNQ moieties stacked as discrete tetrads with interplanar separations of 3.13 and 3.17 Angstrem within the tetrad. Anisotropic d.c. dark conductivity measurements were made and found to be consistent with the structure. c) 1,2-bis(1-hydro-4-pyridinio)ethane (TCNQ)2, DHPA (TCNQ)2, monoclinic, a = 29.481, b = 7.405, c = 13.470 grad., beta = 94.03 grad., Z = 4, space group 2/c. TCNQ moieties arranged in 4 columns of diads along c with an interplanar separation of 3.10 Angstrem within the diad. The structure exhibits hydrogen bonding (N - H--------N heavy atom separation = 2.885 Angstrem) between the cation and TCNQ moieties. d) 1,2-bis(1-hydro-4-pyridinio)ethane (TCNQ)4, DHPA (TCNQ)4, monoclinic, a = 12.894, b = 3.933, c = 27.580 grad., beta = 109.95 grad., Z = 1, space group P 21/c .TCNQ moieties in infinite stacks along b with cations in disordered positions in the channels between the stacks.

Chemical surface modification of cellulose nanocrystals has had a fast development and increased interest from the scientific community as cellulose is the most abundantly available renewable polymer with many advantages such as nanoscale dimensions, high specific strength and modulus, high surface area, unique optical properties and the extraordinary modification potential to increase the application field. This thesis is aimed at expanding and improving upon the current knowledge in order to unlock new applications. Four esterification techniques were applied to the formation of cellulose nanocrystal esters of acrylic acid and methacrylic acid. The degree of surface substitution reached two to three surface hydroxyl groups (the maximum number) available for functionalization and this degree of substitution is very much dependent on the chosen esterification methodology. Two new fluorescently modified cellulose esters based on carbazole-9-yl-acetic acid and coumarin-3-carboxylic acid were synthesised using p-toluenesulfonyl chloride/pyridine and carbodiimide esterifications methods. Absorption and fluorescent properties were also measured and showed fluorescence proportional to the extent of surface functionalization. The maximum theoretically attainable degree of substitution could be reached while still maintaining the crystal structure of cellulose. Cationic cellulose nanocrystals were produced with a high positive surface charge when compared with the literature. The synthesis procedure was attempted in two steps and in a single step. The degree of modification for pyridinium acetate cellulose and methyl imidazolium acetate cellulose was found to depend significantly on the selected pathway. The cationic nature of the modifications was verified using zeta potential measurements and through adsorption of an anion dye. Synthesised cellulose acrylates and methacrylates were used in Thiol-Ene click reactions in which very mild and environmentally friendly reaction conditions proved to work from 10 min reaction times. Four different thiols were added, with and without hexylamine catalyst. In addition, an amidine functionalised cellulose nanocrystal was synthesised based on previously click-modified cellulose in a 2-hour reaction. Furthermore, the switchable behaviour of the synthesised nanoparticles was demonstrated by reverse bubbling with CO2 and Ar.