ABSTRACT

Abstract

The key step in the synthesis of new five, six and seven-membered alicyclic ring [1,2-a]-fused bioreductive benzimidazolequinones was radical cyclisation. Six and seven-membered tributyltin hydride-mediated homolytic aromatic substitutions of nucleophilic N-alkyl radicals onto the benzimidazole-2-position occurred in high yields (63–70 %) when quaternising the pyridine-like 3-N of imidazole with camphorsulfonic acid and using large excesses of the azo-initiator, 1,1′-azobis(cyclohexanecarbonitrile), to supplement the non-chain reaction. Elaboration of benzimidazoles to the benzimidazolequinones occurred in excellent yields. The IC₅₀ values for the cytotoxicity of benzimidazolequinones towards the human skin fibroblast cell line GM00637 were in the nanomolar range, as determined by using the MTT assay. The benzimidazolequinones were much more cytotoxic than indolequinone analogues. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole-6,9-dione was the most potent compound prepared being more than 300 times more cytotoxic than the clinically used bioreductive drug, mitomycin C. The latter benzimidazolequinone was more potent under hypoxic conditions (associated with solid tumors), being 4.4 times more cytotoxic than under aerobic conditions, while mitomycin C was 1.8 times more selective towards hypoxia. The cyclopropane fused pyrido[1,2-a]benzimidazolequinone, 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrido[1,2-a]benzimidazole-5,8-dione was less cytotoxic and selective than the five-membered ring analogue, 1,1a,8,8a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-a]benzimidazole-3,6-dione. Modifying the structure of the most potent pyrido[1,2-a]benzimidazolequinone by attaching methyl substituents onto the quinone moiety increased reductive potentials and decreased cytotoxicity and selectivity towards hypoxia.

Methyl methacrylate (MMA) polymerizations have been conducted in the presence of large excesses of N-tert-butyl-N-[1-diethylphosphono-(2,2-dimethylpropyl) nitroxide] (SG1) at 110°C. It is demonstrated that such a protocol does not improve control/livingness in the nitroxide mediated polymerization (NMP) of this monomer, instead substantial levels of disproportionation between the nitroxide and propagating radical (PMMA^•) results. The extent of the disproportionation reaction increased with the SG1 concentration, eventually becoming the sole end forming event. Significant disproportionation between SG1 and PMMA^• was also observed at substantially lower temperatures (45°C) in the presence of large excesses of SG1. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2194–2203, 2007

Poly(N-Isopropylacrylamide, NIPAM) propagating radicals add to acrylic acid (AA) macromonomer and methacrylic acid polymer containing unsaturated ω-end-group to respectively give novel graft copolymer (represented as • (AA) and ○ (NIPAM) units) and addition fragmentation chain transfer (AFCT). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley. com.]

Summary: Nitroxide-mediated dispersion polymerization of styrene in supercritical carbon dioxide has been performed successfully at 110 °C using a new polymeric so-called inistab species, which fulfils the dual functions of an initiator and a colloidal stabilizer. The inistab species comprised a poly(dimethylsiloxane) block and a polystyrene block end-capped with the nitroxide N-tert-N-butyl-N-[1-diethylphosphono-(2,2-dimethylpropyl)] nitroxide (SG1). The dispersion polymerization resulted in sub-micron sized polymer particles and polymers of narrow polydispersity.

The copolymerization of N-isopropylacrylamide (NIPAM) and N-tert-butylacrylamide (TBAM) via conventional radical polymerization and nitroxide-mediated polymerization (NMP) with N-tert-butyl-N-[1-diethylphosphono-(2,2-dimethylpropyl)]nitroxide (SG1) was investigated. The monomer reactivity ratios were determined to be 0.58 and 1.00 for NIPAM and TBAM, respectively. The reactivities were approximately the same at 120 and 60 °C in N,N-dimethylformamide (DMF) and toluene, respectively, for the conventional copolymerizations and in DMF at 120 °C for NMP. Controlled/living characteristics for NMP were achieved with a 2,2′-azobisisobutyronitrile/SG1 bimolecular system and a unimolecular polystyrene [poly(STY)]–SG1 macroinitiator in the presence of excess free SG1. Block copolymers of poly(N-isopropylacrylamide-stat-N-tert-butylacrylamide) [poly(NIPAM-stat-TBAM)] with styrene {poly(N-isopropylacrylamide-stat-N-tert-butylacrylamide)-block-polystyrene [poly(NIPAM-stat-TBAM)-block-poly(STY)]} were obtained by chain extension of either poly(NIPAM-stat-TBAM)–SG1 with styrene or poly(STY)–SG1 with NIPAM/TBAM. A comparison of the number-average molecular weight calculated from the end-group content with the number-average molecular weight measured by gel permeation chromatography for poly(NIPAM-stat-TBAM)-block-poly(STY)–SG1 indicated that nearly all poly(NIPAM-stat-TBAM) chains were capped by SG1 and were thus living. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 6410–6418, 2006

Summary: A detailed investigation of chain transfer to polymer during free radical ring-opening polymerization of the eight-membered disulfide monomer 2-methyl-7-methylene-1,5-dithiacyclooctane (MDTO) is presented. It has been shown that extensive chain transfer to polymer occurs involving both poly(MDTO) radicals and cyanoisopropyl radicals. Significant decreases in molecular weight were observed when cyanoisopropyl radicals were generated in the presence of poly(MDTO) in the absence of monomer. The molecular weight distribution (MWD) obtained from polymerization of MDTO in the presence of pre-added poly(MDTO) was markedly different from that obtained without pre-added polymer. A kinetic model was constructed in an attempt to quantitatively describe the chain transfer to polymer process based on the addition fragmentation chain transfer mechanism. It was found however that the simulated MWDs were considerably broader than the experimental MWDs, which were similar to the Schulz-Flory distribution.

Summary: Macromonomers have been prepared by polymerization of acrylic acid (AA) and tert-butyl acrylate (tBA) in the presence of the addition-fragmentation chain transfer (AFCT) agents, ethyl α-(bromomethyl)acrylate (EBMA) and tert-butyl α-(bromomethyl)acrylate (BBMA). Chain transfer constants of 1.25 (EBMA) and 1.14 (BBMA) in the AA polymerization, and 2.42 (EBMA) and 1.75 (BBMA) in the tBA polymerization were obtained. The reduction in molecular weight with increasing concentration of AFCT agent and efficient introduction of 2-carbalkoxy-2-propenyl ω-end group was indicative of macromonomer formation. Polymerizations were retarded with increasing concentrations of AFCT agent and increases in the absolute concentration of EBMA slowed down the polymerization of AA but not tBA. The difference between EBMA and BBMA was less significant with tBA; more efficient macromonomer synthesis was indicated by less retardation and greater double bond retention at higher conversions. Copolymerizations of poly(AA) and poly(tBA) macromonomers with styrene indicated that the former was more reactive towards the St propagating radical. The results are rationalized in terms of the steric hindrance imposed by the tert-butyl group. Poly(tBA) macromonomer was successfully hydrolyzed to give an alternative route to the poly(AA) macromonomer.

Summary: The controlled/living radical polymerizations of methyl acrylate in 50% v/v of an ionic liquid initiated by the alkoxyamine generated in situ from 4-oxo-2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (4-oxo-TEMPO) and 2,2′-azoisobutyronitrile (AIBN) at 140–155 °C are reported. The number-average molecular weights increased linearly with conversion, and polydispersity indices are approximately 1.4 in the best case. The rates of polymerization were greater than in anisole, and similar to the rate of spontaneous polymerization in the ionic liquid.

Styrene radical polymerizations mediated by the imidazolidinone nitroxides 2,5-bis(spirocyclohexyl)-3-methylimidazolidin-4-one-1-oxyl (NO88Me) and 2,5-bis(spirocyclohexyl)-3-benzylimidazolidin-4-one-1-oxyl (NO88Bn) were investigated. Polymeric alkoxyamine (PS-NO88Bn)-initiated systems exhibited controlled/living characteristics at 100–120 °C but not at 80 °C. All systems exhibited rates of polymerization similar to those of thermal polymerization, with the exception of the PS-NO88Bn system at 80 °C, which polymerized twice as quickly. The dissociation rate constants (k_d) for the PS-NO88Me and PS-NO88Bn coupling products were determined by electron spin resonance at 50–100 °C. The equilibrium constants were estimated to be 9.01 × 10⁻¹¹ and 6.47 × 10⁻¹¹ mol L⁻¹ at 120 °C for NO88Me and NO88Bn, respectively, resulting in the combination rate constants (k_c) 2.77 × 10⁶ (NO88Me) and 2.07 × 10⁶ L mol⁻¹ s⁻¹ (NO88Bn). The similar polymerization results and kinetic parameters for NO88Me and NO88Bn indicated the absence of any 3-N-transannular effect by the benzyl substituent relative to the methyl substituent. The values of k_d and k_c were 4–8 and 25–33 times lower, respectively, than the reported values for PS-TEMPO at 120 °C, indicating that the 2,5-spirodicyclohexyl rings have a more profound effect on the combination reaction rather than the dissociation reaction. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 327–334, 2003

The 2,6-spirodicyclohexyl substituted nitroxide, cyclohexane-1-spiro-2′-(3′,5′-dioxo-4′-benzylpiperazine-1′-oxyl)-6′-spiro-1″-cyclohexane (BODAZ), was investigated as a mediator for controlled/living free-radical polymerization of styrene. The values of the number-average molecular weight increased linearly with conversion, but the polydispersities were higher than for the corresponding 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) and 2,5-bis(spirocyclohexyl)-3-benzylimidazolidin-4-one-1-oxyl (NO88Bn) mediated systems at approximately 2.2 and 1.6 at 100 and 120 °C, respectively. These results were reflected in the rate coefficients obtained by electron spin resonance spectroscopy; at 120 °C, the values of the rate coefficients for polystyrene-BODAZ alkoxyamine dissociation (k_d), combination of BODAZ and propagating radicals (k_c), and the equilibrium constant (K) were 1.60 × 10⁻⁵ s⁻¹, 5.19 × 10⁶ M⁻¹ s⁻¹, and 3.08 × 10⁻¹² M, respectively. The value of k_d was approximately one and two orders of magnitude lower, and that of K was approximately 20 and 7 times lower than for the NO88Bn and TEMPO adducts. These results are explained in terms of X-ray crystal structures of BODAZ and NO88Bn; the six-membered ring of BODAZ deviates significantly from planarity as compared to the planar five-membered ring of NO88Bn and possesses a benzyl substituent oriented away from the nitroxyl group leading to a seemingly more exposed oxyl group, which resulted in a higher k_c and a lower k_d than NO88Bn. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3892–3900, 2003