Synthetic and structural studies on quaternary ammonium compounds

Smail, Gordon A (1966) Synthetic and structural studies on quaternary ammonium compounds. PhD thesis, University of Glasgow.

Abstract

Part I of the thesis describes the preparation of some linear tris-onium ethers and Part II spectral studies on acetylcholine and related compounds. The influence of chemical structure upon biological activity is the unifying concept. In Part I a general review of the development and use of neuromuscular blocking agents serves as an introduction to the receptor theory of neuromuscular blocking activity end to a survey of natural and synthetic neuromuscular blocking agents containing ether linkages. To extend previous studies on the influence of alphatic ether linkages on the muscle relaxant activity of bis- and tris-onium salts come linear tris-onium compounds possessing an asymmetric ether linkage have been synthesised. A new method has been devised for the synthesis of 3-alkoxypropylamines and 3-alkoxybutylamines. The base catalysed addition of dialkylaminoethanols and dialkylaminopropanols to N-alkylacrylamides and N-alkylcrotonamides afforded respectively 3-dialkylaminoalkoxy-propion-N-alkyl-amides and -butyr-N-alkylamides. The relationship between these additions and the Michael addition is discussed. Reduction of the propion-N-alkylamides and butyr-N-alkylamides with lithium aluminium hydride gave the 3-alkoxypropylamines and 3-alkoxybutylamines but cleavage of the ether linkage also occurred. The reduction of 3-(2-diethylaminoethoxy) propion-N-ethylamide yielded 3-(2-diethylaminoethoxy)propyl-ethylamine, N,N'-diethyl-1,3- diaminopropane, 2-diethylamino-othanol, a polymeric amide and an unidentified amine. A mechanism for the cleavage is proposed. Some bis-(3-alkoxy propyl)-alkylamines and a bis-(3-alkoxybutyl)ethylamins, the triamines required for quaternisation, have similarly been synthesised. The attempted preparation of 3-(2-diethylaminoethoxy)-propionie acid by the addition of 2-diethylaminoethanol to ethyl serylate gave chiefly 2-diethylaminoethyl acrylate, 2-diothylminoethyl 3-ethoxypropionate, and 2-diethylamino-ethyl 3-(2-diethylaminoethoxy)propionate. Acid hydrolysis of 3-(2-diethylaminoethoxy)propionitrile caused appreciable cleavage of the ether linkage. Tontativo mechanisms have been advanced for both reactions. The ultraviolet spectra of acrylamide, cretenamide and some of their N-substituted derivatives have been recorded. N-Alkyl and N, N-dialkyl substitution in the acrylamide series is accompanied by the appearance of new bands. The effect of N-substitution is less obvious in the erotonamide series. The triamines were readily quaternised but many of the salts were hygroscopic. These tris-onium ethers have not yet been tested pharmacologically but may provide information on the suggested anti-bonding effect of ether oxygen atoms at the myonearal synaptic receptor. In Part II the biological actions of acetylcholine arc reviewed and the possible role of conformational isemerism in its biological activity is discussed. Kinetic and infrared studies in the literature may be rainterprated to mean that the quasi-ring form of acetylcholine exists in ethanolic and aqueous solution. The hypothesis is advanced that the quasi-ring conformation is involved at the "muscarinie" receptor and that the extended conformation is complomantery to the "nicotinic" receptor. To establish whether two conformations of acetylcholine co-existed in solution infrared studies of the N-mathyl C-H stretching and deformation frequencies and of the carbonyl stretching frequencies of acetylcholine and related compounds were undertaken. No suitable solvent could be found for the examination of the C-H stretching and deformation frequencies. Infrared spectra were accordingly measured in the solid state for the trimathylammonium salts and these were compared with the spectra of some of the corresponding tertiary bases measured in the liquid state. The spectra were complex in the 3100-2700 cm-1 region. No effect attributable to the influence of either a quaternary nitrogen atom or to intramolecular NC-H-O hydrogen bonding on the C-H stretching frequencies was apparent. The examination of the C-H deformation frequencies provided some evidence for NC-H-O bonding in acetylcholine, acetyl-methylcholine and succinylcholine but the results are not unambiguous Solution spectra of acetylcholine and acetyl-methylcholine in dry dioxan showed split cerbonyl abeorptions. Low intensity absorption, indicative of hydrolysis, precluded definite assignment of these absorptions to conform atonal effects. A series of acetoxyalkyl sulphones formally related to acetylcholine have been synthesised. From measurements of their carbonyl absorptions in dry dioxan the high frequency carbonyl absorption of acetylcholine is best interpreted by inductive effects. The N.N.R. spectra of acetylcholine and acetyl-methyl-choline in D2O solution gave no indication of intramolecular NC-H-O hydrogen bonding.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: J B Stenlake
• Keywords: Organic chemistry
• Date of Award: 1966
• Depositing User: Enlighten Team
• Unique ID: glathesis:1966-72248
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 24 May 2019 15:12
• Last Modified: 24 May 2019 15:12
• URI: https://theses.gla.ac.uk/id/eprint/72248