X-Ray, Quantum Mechanics and Density Functional Methods in the Examination of Structure and Tautomerism of N-Methyl-Substituted Acridin-9-amine Derivatives

Abstract

X-Ray diffraction has shown that N,N-dimethylacridin-9-amine (4) and N ,10-dimethylacridin-9-imine (5) both crystallize in the monoclinic space group P21/c (No. 14) with four molecules in the unit cell. The dimethylamino group in (4) is twisted through an angle of 58·6° relative to a nearly planar acridine moiety. On the other hand, the central ring in (5) is folded along the C(9) · · · N(10) axis through an angle of 26·3° and the exocyclic nitrogen atom with the methyl group attached to it is directed away from the concave side of the acridine nucleus. Theoretical ab initio Hartree–Fock (HF) and semiempirical (MNDO, AM1, PM3) quantum mechanics, as well as density functional (DFT) methods predicted that the N,N-dimethylacridin-9-amine molecule is planar within the acridine moiety and exhibits Cs symmetry, while the other four derivatives originating from the amino or imino tautomeric forms of acridin-9-amine do not have any symmetry elements. Molecules retaining the amino constitution are thermodynamically somewhat more stable than those arising from the imino form. The negative LUMO and HOMO energies, both predicted at the semiempirical level of theory and at the HF level in the latter case, imply that the relevant states are electronically stable. The comparable thermodynamic stabilities of both types of derivatives, as well as the fact that they can be synthesized, undoubtedly speak in favour of the existence of tautomeric phenomena in acridin-9-amine

9-(Trichloroacetylimino)acridine monohydrate

“…The possibility of ®nding an N exo -substituted 9-aminoacridine whose imino form is more stable than its amino form was indicated by Gurevich & Sheinker (1962), and is reinforced by the fact that we synthesized and determined the structure of 10-methyl-9-(methylimino)acridine, i.e. a blocked derivative of 9-iminoacridine (Rak et al, 1998). 9-Aminoacridines, with a well recognized biological relevance, are able to interact speci®cally with molecules in their immediate environment.…”

“…1.7 (3) À4.0 1.0 (3) 22.3 2Notes: (I) 9-(trichloroacetylimino)acridine monohydrate (this work); (II) 9-acridinamine hemihydrate (Chaudhuri, 1983); (III) 9-(tert-butylamino)acridine (Meszko et al, 2002); (IV) 9-(phenylamino)acridine (Leardini et al, 1998); (V) 9-(dimethylamino)acridine (Rak et al, 1998); (VI) 10-methyl-9-(methylimino)acridine (Rak et al, 1998 (Kuma, 1989); cell refinement: KM-4 Software; data reduction: KM-4 Software;…”

“…amino or imino, in the gaseous and liquid phases (Rak et al, 1997), while only the amino tautomer is present in the crystalline phase (Chaudhuri, 1983). Theory also predicts the co-existence of tautomeric forms in 9-aminoacridines monosubstituted at the exocyclic N atom (Rak et al, 1998). The structures of only two such derivatives have been determined, namely 9-(tert-butylamino)acridine (Meszko et al, 2002) and 9-(phenylamino)acridine (Leardini et al, 1998).…”

9-(tert-Butylamino)acridine

“…Its crystals were found to be composed of molecules of the amino tautomeric form (Leardini et al, 1998). We have determined the structures of 9-(dimethylamino)acridine (blocked amino form) and 9-(methylimino)-10-methylacridine (blocked imino form), which prove that 9-aminoacridine derivatives can be obtained, by synthesis, in both tautomeric forms, and both kinds of tautomers can indeed exist in the crystalline phase (Rak et al, 1998). The aim of the present investigation was to check how far bulky substituents, such as tert-butyl, at the exocyclic N atom, affect the ability of 9-aminoacridines to exist and crystallize in either the amino or the imino form.…”

“…Comment 9-Aminoacridine in the gaseous and liquid phases can potentially exist in amino or imino tautomeric forms (Rak et al, 1997), even though it has been established that only the amino tautomer is present in the crystalline phase (Chaudhuri, 1983). Theory also predicts the co-existence of tautomers in the case of 9-aminoacridines substituted at the exocyclic N atom (Rak et al, 1998). It is thus interesting to determine which of the two forms exists in the crystal for any particular derivative.…”