The effects of a-substituents on sodium-ion selectivities of bis(12-crown-4-methyl) malonates, which are highly selective for sodium ions, were investigated by incorporating various substituents with high lipophilicity, bulkiness, polarity and back strain. The incorporation of geminal substituents such as long alkyl chains and benzyl groups into the a-position of the malonate was found to generally enhance the Na+ selectivity, especially against K+, of the bis(12-crown-4) derivatives. The a,a'-dibenzylmalonate derivative gave the best Na+ selectivity of all the bis(crown ether)s designed here.Keywords Bis(12-crown-4) derivatives, a-substituent effect, sodium ion selectivity, ion-selective electrode Monocyclic polyethers, so-called crown ethers, often possess only limited ion selectivities as neutral carriers for ion-selective electrodes. Bis(crown ether) derivatives, a class of macrobicyclic polyethers, are able to bind certain metal ions that are a little larger than their crown cavity powerfully by cooperative action of their two adjacent crown rings on cation complexation.l It was found by our group in 1979 that bis(15-crown-5) derivatives, when applied as neutral carriers for K+-selective electrodes, show prominent ion selectivities.2 Since then, extensive research has been done concerning neutral carrier-type ion-selective electrodes based on bis(crown ether) derivatives.3Malonate ester-type Bis(12-crown-4) derivatives, bis-(12-crown-4-methyl) malonates like 1-3 are much more selective for Na+ than the corresponding monocyclic crown ethers due to the above-mentioned bis(crown ether) effect.4 Specifically, Bis(12-crown-4-methyl) 2-dodecyl-2-methylmalonate 1, which is now commercially available, is an excellent neutral carrier for plasticized poly(vinyl chloride) (PVC) membrane Nat-selective electrodes of practical use. The study has suggested that the existence of the a-substituents on malonate derivatives is quite important for high Na+ selectivity of the malonate ester-type Bis(12-crown-4)s. This prompted us to modify the a-substituents of the Bis (12-crown-4) and to compare Na+ selectivities of the resulting bis(12-crown-4) derivatives as the neutral carriers. This paper is concerned with the design of Bis(12-crown-4-methyl) malonates carrying various a-substituents, 4 -15, and comparisons of their Na+ selectivities as neutral carriers for ion-selective electrodes. ExperimentalSyntheses of Bis(12-crown-4) derivatives Malonic diethyl esters with two identical a-substituents were prepared by the reaction of diethyl malonate with two equimolar amounts of an alkyl bromide in the presence of sodium ethoxide. Similarly, the diethyl esters with two different a-substituents were obtained by the reaction of diethyl malonate successively with one equimolar amount of two different alkyl bromides. Diethyl benzalmalonate was prepared by the treatment of diethyl malonate with benzaldehyde in benzene in the presence of piperidine and was then hydrolyzed to its corresponding diacid with sodium hydroxide in ethanol. Th...

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The 5N-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (a 1 R,a 2 R)-and (a 1 S,a 2 S)-atropisomers with extraordinary stability (ΔG ⧧ = ∼130 kJ/mol) by freezing the conformation around the sp 2 −sp 2 axis in an Ar−N(SO 2 ) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (a 1 R*,a 2 R*,3R*). The (a 1 S) stereochemistry was crucial for exerting the antiproliferative activity.

5N-Acylation of 1N-methyl-1,5-benzodiazepin-2ones with (S)-2-phenylpropanoyl and (S)-2-phenylbutanoyl chlorides afforded the (a 1 S,a 2 S,S)-atropisomer (I) diastereoselectively over the (a 1 R,a 2 R,S)-isomer (II) in the ratio of 1:0.06−0.15. The preferential formation of I may be explained by the thermodynamically preferable π−π stacking interaction between two benzene rings in the benzodiazepine ring and the acyl chloride during the reaction. Analysis using ab initio calculations (RI-MP2/ 6-31+G(d) level of theory) for the acylation reaction indicated the π−π stacking interaction in the transition state. Furthermore, isomer I was shown to be thermodynamically more stable than II. The higher stability of I may be caused by the folded form of the two benzene rings, which was revealed by NMR, X-ray, and computational analyses.