Aggregation behavior of cholic acid derivatives in organic solvents and in water

H.M. Willemen

Research output: Thesisinternal PhD, WU

Abstract

<p> In this thesis various cholic acid derivatives are reported that display aggregation in water or in organic solvents. Spontaneous aggregation of single molecules into larger, ordered structures occurs at the borderline of solubility. Amphiphilic compounds, or surfactants, which possess a hydrophobic as well as a hydrophilic part, have a high tendency to form aggregates to minimize unfavorable polar-apolar interactions with the surrounding solvent. There are different types of aggregates in water as well as in organic solvents. Examples of aggregates in water are micelles and vesicles. The apolar tails of the surfactants are located in the interior of these aggregates, shielded from water, and the polar head groups are located on the surface. The shape of the surfactant determines for a large part the shape of the aggregate. An example of an aggregate in organic solvents is the organogel. Fibers can be formed by means of various interactions between the single organogelator molecules and these fibers then build a network. A small amount of organogelator is sufficient to increase the viscosity of the solvent.</p><p> Cholic acid is a main bile acid, a special class of micelle-forming biosurfactants. It has a carboxylate group as an ionic head group attached to a steroid unit via a small spacer. The steroid unit is facial amphiphilic due to the presence of three hydroxyl groups, which are all located on one side. Cholic acid can be easily derivatized via the carboxylate group and hydroxyl groups. In this thesis numerous newly synthesized cholic acid derivatives are reported of which the aggregation behavior in solution has been studied. Special emphasis is on the variation in molecular structure and its influence on aggregation properties.</p><p> A large number of cholic acid derivatives with either an amino acid ester group or a long alkyl group attached to the carboxylic acid group via an amide bond display organogel formation in various organic solvents, mostly aromatic solvents. Both types of compounds form thermoreversible gels that are completely transparent and stable for prolonged periods of time. The sensitivity of the gels toward water suggests the construction of a hydrogen bonded gel network. Molecular variation and infrared spectroscopy confirm this and show that both the amide bond and the hydroxyl groups are involved. Electron microscopy shows the presence of thin fibers. From SANS measurements the diameter of the fibers was established to be around 20 to 40 Å, so the fibers are monomolecular in thickness. Further details about the fibrous shape and network structure were also gained by SANS. Derivatives with an alkyl tail or an amino acid butyl ester form flat fibers that are connected via loose entanglements. Derivatives with an amino acid methyl ester group form round fibers that are connected via crystalline knots of about 100 to 200 Å. This last type of gel network breaks down stepwise upon heating, which could be monitored with DSC.</p><p> Small variations in the molecular structure of these organogelators could induce a change in the gelation behavior. Introduction of an aromatic unit in the alkyl tail limits the number of solvents, suited for gelation. Reversing the amide bond increases the melting point of the gels. The stereochemistry of the amino acid unit seems to play a role in some compounds. After substitution of the amide group by a urea group a longer alkyl tail is necessary for gelation, whereas after substitution by an ester group no gelation occurs in aromatic solvents. These alkyl ester derivatives, however, are capable of forming a two-component gel in hexane and octane, in the presence of isomannide or isosorbide. The optimal ratio for the two components is 1:1.</p><p> Hydrolysis of the alkyl ester group of several cholyl amino acid ester derivatives creates a series of compounds analogous to the natural bile salt glycocholate. These water-soluble compounds form small micelles of about 5 nm. Only a small variation in the cmc values was found for the various compounds, although the amino acid side groups range from a single hydrogen atom to an aromatic unit or an ionic group. The cmc value of the tyrosine derivative undergoes a small increase at high pH.</p><p> Another series of micelle forming cholic acid derivatives was prepared in which the amphiphilicity of cholic acid was completely altered. A long alkyl tail was attached to the carboxylic acid group and ionic groups were attached to the hydroxyl groups via alkyl spacers, resulting in compounds with three ionic head groups. These are the first facial amphiphiles based on cholic acid with three permanent ionic groups. These compounds form micelles in water and the size of the micelles is dependent of the alkyl tail length. Increasing the length of the spacer or of the alkyl tail causes a decrease in cmc, although the decrease is not as large as found for other surfactants. The thermodynamics of micellization was studied using ITC and the temperature-dependent behavior of these compounds is comparable to other surfactants. Some of these compounds have a strong inhibitory effect on the growth of gram-positive and gram-negative bacteria. In their antimicobial activity they are comparable to some other facial amphiphiles with nitrogen-containing groups.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • Sudhölter, E.J.R., Promotor, External person
  • Marcelis, A.T.M., Promotor
Award date8 Oct 2002
Place of PublicationS.l.
Print ISBNs9789058087140
Publication statusPublished - 2002

Keywords

  • cholic acid
  • derivatives
  • solvents
  • gelation
  • micelles
  • physical state

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