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A set of structures encompassing 1-(9-acridinyl)thiosemicarbazide and its 2-methyl derivative together with their various tautomeric structures; the 5-membered ring 1,3-thiazolidin-4-one products resulting from the reaction of 1- (9-acridinyl)thiosemicarbazide and its 2-methyl derivative with dimethyl acetylenedicarboxylate (DMAD) together with the alternative 6-membered ring isomeric reaction products as well as other potential isomeric structures; and the 6- membered ring 1,3-thiazin-4-one product resulting from the reaction of 2-methyl-1-(9-acridinyl)thiosemicarbazide with methyl propiolate (MP) together with the alternative 5-membered ring isomeric reaction product were all extensively studied by molecular modeling calculations using DFT at the B3LYP/6-31G(d,p) level of theory. The ring-chain tautomerism of the thiosemicarbazides, the regio- and stereoselectivity of the reactions, the adopted conformations and E/Z configurations of the products, the prototropic tautomerism of all the compounds, and the reasons for the predominance of the s-cis conformation of the Z configuration of the 1,3-thiazolidin-4-one product in particular were all extensively analyzed. Comparison of the modeled structures were also made to the 1,3-thiazolidin-4-one and 1,3-thiazin-4-one structures of the methyl derivative as well as 1-(9-acridinyl)thiosemicarbazide available from X-ray crystallographic analysis. Tactics utilizing spectroscopic methods {IR frequencies (;) and NMR chemical shifts (;), scalar coupling constants (J), and NOEs (;)} in conjunction with molecular modeling calculations of the spectral parameters {frequency calculations (;) and NMR ; using the GIAO method and J by calculation of the Fermi contact term} were evaluated in terms of proving 5- or 6-membered ring formation.
The regioselectivities of methyl- and phenylhydrazine with acridin-9-yl isothiocyanate (thus yielding thiosemicarbazides with acridine substituted on the urea-type side) were examined. Methythydrazine regioselectivity was high with the alpha-nitrogen atom overwhelmingly more nucleophilic than the beta-nitrogen atom; phenylhydrazine regioselectivity was poor but varied with the solvent and only in the case of ethanol was nucleophilic predominance of the alpha-nitrogen atom pronounced. Of note, whilst both phenyl thiosemicarbazides were present in solution only as spiro forms, the methyl product was present as an equilibrium mixture of open-chain and spiro thiosemicarbazides. Reactions on the NH2 blocked analogue of methyl acridin-9-ylthiosemicarbazide (1-isopropylidene-2- methylthiosemicarbazide) were also examined. Interestingly, present in the starting material itself was a structural motif of novelty wherein a triazolethione represented the major species of an equilibrium between cyclic and open-chain forms
The reaction of methyl acridin-9-ylthiosemicarbazide under basic conditions with methyl bromoacetate resulted in a 1,3-thiazolin-4-one structure as provided by X-ray crystallography. The structure forced a re-evaluation of the reactant methyl acridin-9-ylthiosemicarbazide, originally thought to be 2-methyl 4-acridin-9-ylthiosemicarbazide based on synthetic expectations, but which when examined by X-ray crystallography was found to be in fact the isomeric 2- methyl 1-acridin-9-ylthiosemicarbazide resulting from rearrangement via a spiro form which it is in equilibrium with in solution. The product resulting from reaction with methyl iodide was also studied and the previously reported semicarbazide produced by reaction with MNO was re-examined. In both cases, the 1,2 isomer rather than the 2,4 isomer was found to be present based on the sign of the 3JCH3,N11 coupling. Full characterization of the compounds was rendered by 1H, 13C, and 15N solution-state NMR, and in the solid state, by both 13C and 15N NMR.
The configuration and dynamic behavior of O-allyl-S-methyl-N-(acridin-9-yl)iminothiocarbonate (1) and its S- allyl-O-methyl regioisomer (2) were studied using quantum chemical calculations and by applying a novel graphical method to scatter maps obtained from MD simulations for evaluation of an NOE-weighted internuclear distance (r(NOE)). Energy calculations indicated that the Z configuration was predominant for each compound and, further, this was supported both by the calculated chemical shifts and the rNOE. Both N-inversion- and rotation-type transition-state structures were also calculated for the E/Z isomerization process, the results indicating that the preferred interconversion mechanism for 1 is N-inversion, but contrastingly, interconversion via rotation is equally as probable as N-inversion for 2. This supports the notion that one or the other or both pathways can be active and each system needs to be assessed on a case- by-case basis. Copyright (c) 2005 John Wiley & Sons, Ltd
A set of structures encompassing 1-(9-acridinyl)thiosemicarbazide and its 2-methyl derivative together with their various tautomeric structures; the 5-membered ring 1,3-thiazolidin-4-one products resulting from the reaction of 1- (9-acridinyl)thiosemicarbazide and its 2-methyl derivative with dimethyl acetylenedicarboxylate (DMAD) together with the alternative 6-membered ring isomeric reaction products as well as other potential isomeric structures; and the 6- membered ring 1,3-thiazin-4-one product resulting from the reaction of 2-methyl-1-(9-acridinyl)thiosemicarbazide with methyl propiolate (MP) together with the alternative 5-membered ring isomeric reaction product were all extensively studied by molecular modeling calculations using DFT at the B3LYP/6-31G(d,p) level of theory. The ring-chain tautomerism of the thiosemicarbazides, the regio- and stereoselectivity of the reactions, the adopted conformations and E/Z configurations of the products, the prototropic tautomerism of all the compounds, and the reasons for the predominance of the s-cis conformation of the Z configuration of the 1,3-thiazolidin-4-one product in particular were all extensively analyzed. Comparison of the modeled structures were also made to the 1,3-thiazolidin-4-one and 1,3-thiazin-4-one structures of the methyl derivative as well as 1-(9-acridinyl)thiosemicarbazide available from X-ray crystallographic analysis. Tactics utilizing spectroscopic methods {1R frequencies (nu) and NMR chemical shifts (delta), scalar coupling constants (J), and NOEs (eta)} in conjunction with molecular modeling calculations of the spectral parameters (frequency calculations (v) and NMR 6 using the GIAO method and J by calculation of the Fermi contact term) were evaluated in terms of proving 5- or 6-membered ring formation.