A structural investigation on the flexibility of certain o-phthalic acid derivatives
Introduction
In a recent paper we envisaged and discussed the possibility to design chemical libraries for broad screening purposes on the basis of symmetry considerations and the modulation of thermal flexibility. In particular, the suitability of the trans 3,5-homo-disubstituted piperidine scaffold (Fig. 1a) was studied from the physical-chemical point of view [1]. All trans 3,5-homo-disubstituted piperidines are chiral compounds whose handness originates from the existence of two stereogenic centers on the piperidine ring. Although we focussed our attention on this scaffold just for the robust kinetic stability of the related enantiomers and the synthetic availability of both enantiomeric series, it is clear that the perspective to control the emergence of chirality along a scale of decreasing thermal flexibility would be interesting as well.
In the case of the cited study, we stated that certain chemical transformations could have an effect on the exposure of the appending moieties comparable to that obtainable by lowering the temperature. In the present contribution, we use the same idea to hypothesize that the sequence of compounds of general formulae I–IV in Fig. 1(b) could represent a scale of decreasing ‘thermal’ flexibility, suitable to make chirality to emerge along the sequence itself, possibly intercepting in progressive manner the pharmacological time scale of 15–60 min which features often in vitro bioassays.
Compounds of formula I–III are all examples of o-substituted N,N′-dialkyl benzamides. From a different viewpoint, compounds of general formula I are also examples of o-substituted benzoic esters, while those of general formula III–IV are also examples o-substituted N,N′-dialkyl thiobenzamides. In benzoic esters the structural tendency is that to conjugate the carboxy group with the aromatic ring, giving rise to a planar arrangement of the whole fragment. In N,N′-dialkyl benzamides, flatness is hampered by steric reasons and when the benzamide is o-substituted, the arrangement is axially chiral [2]. Enantiomerization is fast in solution, though, with half life times ≤2 s at room temperature unless another substituent is placed onto the second ortho position [3]. o-Substituted N,N′-dialkyl thiobenzamides are known to conserve the same geometry of the corresponding amides; they are also known to be more rigid and enantiomerization is by far slower than in the oxo series [4]. So, the direct conversion of the amide group into the thioamide one, easily affordable by commercially available reagents, should have the effect to freeze out the internal motions in a progressive manner when bridging from compounds of general formula II to those of formula IV.
Compounds of general formula II and IV should play a particular role in this scheme (Fig. 1b).
When R1=R2, the rotation about the amide (or thioamide) bond brings the molecules into coincidence with themselves (Fig. 2). As for the rotation around the CAr–CO, or CAr-CS bonds, it is known that compounds II prefer the anti arrangement of the amide groups (Fig. 2), possibly because of favourable dipolar interactions [5], [6]. This means that compounds II possess a dissymmetric stable state of similar geometry to that of a trans 3,5-homo-disubstituted piperidine. If the same anti-rule were respected for compounds IV, one could compare the biological performance of species of the same geometry and appending moieties but different enantiomerization times and even hope that the enantiomers foreseeable for compounds IV possess half life times enough high to permit their resolution and biological evaluation as kinetically stable species on the time scale of the bioassay.
With these considerations in mind, we report here on a physical-chemical study, concerning both solid and gas phase, of compounds 1–4 (Scheme 1) that we take as models of compounds of general formula I–IV, under the restriction to the case R1=R2. Actually, the original idea was to use diethyl amine, namely the secondary amine for which R1=R2=CH3 (Fig. 1), along the whole sequence. Unfortunately, both N,N-diethyl-phthalamic acid methyl ester [7] and N,N′-diethyl phthalamide, hereafter 2aEt [8], are known to melt at about 313 K and we did not succeed to grow crystals suitable for X-ray analysis of these compounds. The goal was reached instead by using two constrained analogs of diethylamine, i.e. morpholine and (3R,5R) piperidine-3,5-diol, respectively. By the way, in the literature the X-ray crystal structure of the N,N′-diethyl phthalamide complexed with pentachlorophenol (1:2 ratio) has been retrieved, hereafter PDAPCP [9].
Section snippets
Crystallization procedures
Compounds 1–4 were obtained using standard synthetic methodologies. Crystals suitable for X-rays analysis were collected from methanol/diethyl ether (compound 1), methanol (compound 2), n-hexane (compound 3), and ethyl acetate (compound 4).
Crystal data and refinement
Intensity data of compound 1 were collected on a Siemens P4 four circles diffractometer equipped with a rotating anode and by using a graphite monochromated Cu Kα radiation (λ=1.5418 Å), T=298 K. Data were corrected for Lorentz and polarization effects. For
Solid state studies
Table 2 sums up the results of the crystallographic analyses as a function of the dihedral angles τ1 and τ2, defined as anticipated in Scheme 3. Two molecules are represented for compound 4. This is because two independent molecules were found in the asymmetric unit (see also below in the text). Further, in the last column of Table 2 the data taken from literature were inserted for N,N′-diethyl phthalamide complexed with two molecules of pentachlorophenol (PDAPCP) [9]. As for the changes of the
Conclusions
The leading idea of this work was that the sequence of compounds 1–4 represented a sequence of decreasing flexibility suitable for the generation of chemical libraries directed to make chirality to emerge along the sequence itself. In this paper we have characterised the sequence both experimentally, by X-ray analyses and, partially, calorimetric investigations, as well as theoretically by molecular mechanics and ab-initio calculation. The sequence was also characterised from a statistical
Acknowledgements
The authors thank CRIST (Centro Interdipartimentale di Cristallografia Strutturale) University of Florence where the X-ray measurements were carried on.
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