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A micro-industrial plant of a gas-liquid-solid micro-reaction system is designed and built (constructed), that employs a simple on-chip, single-line monolithic microreactor system constructed in silicon for the heterogeneous hydrogenation of organic liquids, coupled with an in-situ microbubble slug/annular regime generation. The integration of catalyst (Pd) on the channel walls is well described. The organic liquid (nitrobenzene in this case) was syringe-pumped as the main channel flow, whilst the hydrogen gas was introduced through a side pore. Using the nitrobenzene as organic liquid, a reactor channel of 200 µm width and a gas inlet channel of 5 µm width in this work, the gas inlet angle, the liquid in-flow velocity and gas in-flow rate were monitored to optimize the bubble slug (annular flow regime) generation. The 90◦ inlet channel was found to be the optimum angle for the creation of a thin liquid film on the channel wall. The operation of the system for the execution of reactions under pressure, and the system cleaning and system shut-down after experiments, and emergency shutdown procedures for safety purposes are presented. Nitrobenzene hydrogenation reaction yields as high as 93% were achieved with the microplant.

Selectively functionalized calix[4]arenes are used to build effective receptors for cations, anions and neutral molecules or for a combination of a cation and an anion. This was done by combination with a terphenyl unit (cation receptor), a uranyl-containing salen moiety (for anionic and neutral guests) or by introduction of sulfonamide groups (anion receptor). Conformational control is effected using the appropriate conditions for the lower rim alkylation, but the conformation can also be influenced by hydrogen bonding. New routes for the synthesis of selectively functionalized calix[4]arenes bearing a combination of functional groups at the upper rim were developed together with a simple method for the direct introduction of meta substituents. Nitrated calix[4]arenes have very good non-linear optical characteristics. Selective methylation and phosphorylation of p-tert-butylcalix[6]arene is shown to be possible when specific conditions are used. The conformational properties of selectively functionalized calix[6]arenes were studied by 1H NMR spectroscopy. The controlled conformation of 1,3,5-trimethoxy-p-tert-butylcalix[6]arene was used to synthesize a cryptocalix[6]arene.

Combination of medium-sized building blocks comprises a new strategy for the synthesis of artificial receptor molecules. These building blocks should have relatively rigid structures to which functional groups can be attached, such as calix[4]- and -[6]arenes, resorcin[4]arenes, porphyrins, and cyclodextrins. Combination of a (3- cyclodextrin with a calix[4]arene moiety resulted in water soluble receptor molecules. Large multifunctional receptors have been prepared by the covalent combination of two calix[4]arenes and one Zn-tetraarylporphyrin. The controlled conformation of p-tert-butylcalix[6]arenes which are alternately substituted with methoxy groups, was used to synthesize a cryptocalix[6]arene consisting of a calix[6]arene and a cyclotriveratrylene unit. A new type of diastereoisomerism (carceroisomerism) was found during the synthesis of carceplexes constructed from one calix[4]arene and one resorcin[4]arene. In a (2+2)-mode of coupling, the combination of calix[4]arenes and resorcin[4]arenes gave a large rigid receptor molecule of nanosize dimensions (ho/and). The combination of two calix[4]arenes with one resorcin[4)arene resulted in three different compounds (endo-endo, endo-exo, and exo-exo) with large hydrophobic surfaces to which steroids can be complexed.

A general method has been developed for the determination of kinetic stabilities of macrocyclic alkali-metal complexes with rates of decomplexation (k(d)) below 10(-3) s-1, by use of radioactive isotopes. This method offers the possibility to study the influence of the solvent polarity and of the salt concentration in solution on the rate of decomplexation of macrocyclic metal complexes. Further advantages are the small amounts of ligand required for these determinations and the simplicity of the method. Furthermore, it is possible by this method to study the 'degenerate' exchange of sodium for sodium and of rubidium for rubidium. By this method the kinetic stabilities of the sodium and rubidium complexes of calixspherands 1-4 were determined. Calixspherand 3 forms kinetically very stable complexes with sodium and rubidium cations in acetone and Me2SO in the presence of high concentrations of sodium cations in solution; half-life times of exchange are 855 (Na+) and 528 (Rb+) h in acetone and 352 (Na+) and 845 (Rb+) h in Me2SO, respectively. The results of this method were verified by an independent H-1 NMR spectroscopic method.

Organic molecules with π electron systems and asymmetrical charge distribution are interesting tor use in quadratic nonlinear optics. Calix[4]arenes are cyclophanes that consist of four phenol moieties connected by methylene bridges. Functionalization of these phenols allows the combination of four D-π–A units within a single molecule. The increase in the number of D-π-A systems in a calix[4]arene molecule is accompanied by an enhancement of the molecular hyperpolarizability and the dipole moment and by a blue shift of the charge-transfer absorption band. Different substituted calix[4Jarene compounds have been synthesized and examined.

The concept of bioreductive alkylation as a mechanism of action of aziridinylquinoid anticancer agents has been investigated. The influence of quinone substituents on quinone reduction, on protonation of the aziridines prior to and following quinone reduction and on partitioning properties of the compound was examined. Parameters obtained from a combined electrochemical, chemical‐stability and lipophilicity study describing these processes were determined and correlated quantitatively in a Hansch‐type QSAR study with biological data obtained from three experimental tumor models. Poor quantitative correlations between cytotoxicity in a L1210 clonogenic assay and the parameters were obtained. Good linear relationships, however, between antitumor activity in vivo (vs. L1210 leukemic mice and vs. B16 melanoma‐bearing mice) and the lipophilic properties of the quinone were found. These relationships, showing a negative correlation between antitumor activity and lipophilicity, can be used to predict the activity of new, unknown compounds. No trend was evident between antitumor activity and other parameters, although some indications for potential importance of electronic and steric properties of the substituents and of their ability to form hydrogen bonds were found.

The concept of bioreductive alkylation as a mechanism of action of aziridinylquinoid anticancer agents has been investigated by the use of electrochemical techniques. Properly substituted aziridinylquinones are activated by an electrochemical step (reduction of the quinone function), followed by protonation of the aziridinyl moiety to the alkylating species. The influence of substitution on quinone reduction, on protonation and on subsequent opening of the aziridines (prior to and after quinone reduction) has been examined. A series of mono- and poly(1-aziridinyl)-quinones has been synthesized and analyzed by direct current (d.c.) polarography. The half-wave potential (E1/2 value of the quinone reduction and the pKred and pKred2 (reflecting the ease of protonation at the mercury electrode of one and two aziridinyl rings, respectively) were used in a Hammett type QSAR analysis. A linear relationship between E1/2 and the electronic substituent constant ¿p was obtained for simple quinones. Deviations from linearity were observed, due to steric and/or resonance interactions which influence quinone reduction, with amino- and halogen-substituted quinones. Unknown ¿p values could be calculated. Relationship between pKred2 and some physical-chemical parameters show that electronic and steric properties of quinone substituents affect pKred2. In addition, the formation of a hydrogen bond between the quinone substituent and the adjacent aziridinyl ring (which may thwart aziridine protonation) and the presence of a methyl substituent at position 2 of the aziridine (which facilitates protonation) are of importance. Results of this study have lead to a better knowledge of the individual substituents with respect to their electronic and steric influences on quinone reduction and aziridine protonation, which may be of importance if these processes play a decisive role in cytostatic activity as well as toxicity.

The interaction between glutathione and potential anti-tumour 3,6-disubstituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied using u.v. spectrophotometry and h.p.l.c. The formation of BABQ-glutathione adducts was demonstrated in vitro for the BABQ parent compound (TW13), triaziquone (2,3,5-tris (1-aziridinyl)-1,4-benzoquinone) and for BABQ derivatives containing halogen substituents. The clinically-used BABQ derivative diaziquone (AZQ; 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone) did not react with glutathione. TW13 and triaziquone markedly inactivated bacteriophage M13-DNA in the presence of glutathione. This inactivation is probably produced by reductive activation of the BABQ derivative to a DNA-alkylating semiquinone radical. However, formation of bulky glutathione adducts decreases reactivity to DNA. Halogen-substituted BABQ derivatives react rapidly with glutathione to form adducts. This appeared to prevent DNA alkylation by these compounds. Comparison of these results with in vivo and in vitro activity against tumour models (L1210) suggests that in vivo halogen-substituted BABQ derivatives are efficiently inactivated by glutathione conjugation. The differences between the halogen-substituted BABQ derivatives on the one hand and TW13 and triaziquone on the other hand are probably caused by a difference in reaction mechanism with glutathione. From the viewpoint of drug design, halogen-substituted BABQ derivatives are expected to be inactive anti-tumour agents, in spite of high reactivity and activity in tumour models in vitro.

The influence of methyl-, hydroxy and amino substituents on the electrochemical behaviour of simple 1,4-naphtho-and 1,4-benzoquinones, model compounds of many quinoid antitumour agents, in aqueous media was studied. Significant changes in electrochemical behaviour were observed, potentially the result of a change in the electron density of the quinone moiety, pre- or post-protonation of substituents, hydrogen bond formation, tautomerization reactions and steric interactions between the quinone moiety and substituents. The information obtained was of benefit in the elucidation of the reduction mechanisms of quinoid antitumour agents such as aziridnylquinones and mitomycins.

The reduction mechanism of 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone (Diaziquone, AZQ) and several model compounds of the mono- and bis(1-aziridinyl)quinone type at the dropping mercury electrode in aqueous solutions was studied. In addition, the influence of methyl substitution of the aziridinyl moiety at the 2-position on the protonation of the aziridine nitrogen was investigated. Substituent effects on quinone reduction and aziridine protonation prior to and following quinone reduction were studied qualitatively.