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Structural development of self-immolative dendrons for the detection of electrophilic species

Priya, (2018) Structural development of self-immolative dendrons for the detection of electrophilic species. PhD thesis, University of Reading

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Synopsis Chapter 1 introduces self-immolative systems (both dendritic and polymeric systems) that have been used in the fields of drug delivery systems, imaging, and chemo-detectorsion (such as enzymes, electrophiles, nucleophiles, redox and acids or bases). This chapter reveals the details of the methodologies, mechanisms and limitations for the 'classical' release of self- immolative systems (e.g. self-immolative elimination, self-immolative cyclisation, self- immolative amplification reactions). Another class of self-immolative system is also described 'relayed' amplification reactions (so-called 'dendritic chain reactions'). This chapter also covers the synthesis and the significance of self-immolative linear polymeric materials containing functional groups (such as poly(carbamates), poly(phthalaldehyde) (PPHA) and poly(benzyl ethers) as employed in chemo-detector. The main focus of this chapter is the review of self-immolative amplification dendron systems that have been utilised as sensors and chemoselective detection systems. Chapter 2 describes the use of protecting groups used in peptide synthesis ( especially for the reactive amine functionality). In particular, Kunz reported the 2-methylthioethoxy carbonyl protecting group as a water-soluble protecting group suitable for the protection of amine functionalities. In this Chapter, the chemistry of the 2-methylthioethoxy carbonyl was studied and it is referred to throughout the thesis as the 'Kunz trigger group' as it was the platform for the development of self-immolative systems specific to electrophiles (such as mustard gas). This Chapter reports the optimisation of the conditions for protection and deprotection strategies (alkylation via addition of methyl iodide and P-elimination (i.e. addition ofDIPEA)). These strategies started with simplest amino acid, glycine. The degradation of the glycine methyl ester protected with the Kunz trigger group was performed in both presence and absence of silver hexafluoroantimonate (AgSbF6 or silver salt) and in both CD3CN and D20 solvents. The results revealed that the rate of alkylation of the Kunz protected glycine methyl ester was minimal in absence of the silver salt in both the CD3CN and D20 solvents. Chapter 3 reports the synthesis of an AB type of non-amplified self-immolative system equipped with Kunz trigger group and methodology was used for the degradation of an AB dendron (utilising the optimised conditions described in Chapter 2). The synthesis of an AB non-amplified systems started with 4-hydroxybenzyl alcohol linked with self-immolative linker (i.e. Boe-protected amine) and N-methyl-4-nitroaniline as the reporter unit. To observe the stability and sensitivity of an AB non-amplified self-immolative system (in mixture of solvents), the degradation studies were carried out under four different reaction conditions in the absence and presence of the silver salt and CD3CN/D20 (9: 1) solvents mixture. Again, it was found that degradation (i.e. alkylation and P-elimination) reactions were dramatically improved in the presence of silver. Additionally, as desired, the degradation studies revealed the release of N-methyl-4-nitroanilide (via observation of a vibrant yellow colour in solution). However, the P-elimination step did not afford clear evidence for release of N, N'-dimethylurea derivative and 4-hydroxybenzyl alcohol phenoxide motifs. Therefore, a model compound was synthesised, and degradation studies were carried out in presence of tetrabutylammonium fluoride trihydrate (TBAF.3H20) and spray dried potassium fluoride (KF). Under these conditions, the model compound showed the majority of a new compound occurs as a result of reattachment of the N-methyl-4-nitroaniline and 4-hydroxybenzyl alcohol after decarboxylation. Whereas, the presence of symmetric and asymmetric oligomer was also observed. Chapter 4 describes the development and synthesis of an AB2 type of a cresol based amplified self-immolative dendron containing two units of the self-immolative linker (i.e. Boe-protected amine) and N-methyl-4-nitroaniline as the reporter units. The results from Chapter 2 and Chapter 3 highlighted the poor conversion of the alkylation step in absence of the silver salt, therefore, in this Chapter alkylation study was not performed (in absence of the silver salt). This Chapter reports the effect of the polarity of solvents used in the degradation studies (solvent mixtures used were; 9: 1, 8:2 and 7:3 CD3CN/D20) on the stability and sensitivity of the an AB2 type cresol based amplified self-immolative dendron in both the alkylation and P-elimination reactions. The results obtained after performing degradation under theses solvent conditions showed that 7:3 CD3CN/D20 enabled the fastest rate of alkylation among all of the solvent mixture conditions examined.

Item Type:Thesis (PhD)
Thesis Supervisor:Hayes, W. and Russell, A.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:85059

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