Synthesis, molecular structure, electrochemistry and DFT study of a ferrocenyl-substituted 4-quinazolinone and related heterocycles†

2-Ferrocenyl-4(3H)-quinazolinone (2) was obtained by acylation of 2-aminobenzoic amide with ferrocenecarbonyl chloride (FcCOCl) and subsequent base-catalysed cyclisation of the intermediate 2-(ferrocenecarboxamido)benzamide (1). The related benzoxazin-4-one (4) was obtained analogously (though in one step) from FcCOCl and 2-aminobenzoic acid. Compounds 2 and 4 were thionated with P2S5 to give the corresponding ferrocenylated 4(3H)-quinazoline thione (3), and a mixture of benzothiazine-4-thione (5) and benzothiazine-4-one (6, major), respectively. Attempts to prepare 3-amino-2-ferrocenyl-4(3H)-quinazolinone from 4 and hydrazine hydrate failed. The reaction gave only 2-(ferrocenecarboxamido)benzohydrazide (7), which reacted with 2-chloro-1,3-dimethylimidazolidinium chloride to afford a mixture of cyclic and open (major) condensation products, both bearing the 1,3-dimethylimidazolidin-2-ylidene terminal group (8 and 9). All compounds were characterised by spectroscopic methods and the molecular structures of 1–7 and 9 were determined by X-ray diffraction analysis. Cyclic voltammetric measurements revealed that the compounds undergo a single one-electron oxidation, localised presumably at the ferrocene unit. DFT computations for 2 as a representative example performed in the gas phase and crystal state, reproduced well the experimental geometry and further supported the assignment of the redox processes.


Introduction
Studies dealing with the preparation of ferrocenylated heterocycles 1 emerged shortly after the discovery of ferrocene, 2 very likely in response to the important role which the uniquely large and diverse family of the conventional (i.e., organic) heterocyclic compounds has always played in chemistry. 3owadays, the studies into ferrocenyl-substituted heterocycles are motivated mostly by the search for new heterocyclic compounds and ligands 4 and, further, by prospective applications of the specific electrochemical properties 5 and biological activity of these compounds. 6lthough the structurally related ferrocenyl quinolines, 7 quinolinones, 8 flavones 9 and quinoxalines 10 have been already described, there is, up to the best of our knowledge, no report available in the literature concerning the structurally related, ferrocenyl-substituted quinazolinones and similar compounds, which all represent the basis of various biologically active substances. 11This prompted us to prepare and structurally characterise the directly ferrocenyl-substituted quinazolinone, viz.2-ferrocenyl-4(3H)-quinazolinone (2), its corresponding 3,1-benzoxazin-4-one and their thionated analogues.Details of our investigations are presented in this contribution.

Results and discussion
Synthesis of 2-ferrocenyl-4(3H)-quinazolinone and the related compounds 2-Ferrocenyl-4-quinazolinone (2) was synthesised in the conventional manner 12 as shown in Scheme 1.In the first step, 2-aminobenzoic amide was acylated with ferrocenecarbonyl chloride to give bis-amide 1. Upon treatment with NaOH in a methanol-water mixture, intermediate 1 underwent smooth heterocyclisation to afford quinazolinone 2 as an orange solid (76% isolated yield over the two steps).Compound 2 was further thionated with phosphorus pentasulphide 13 in the presence of triethylamine to give the respective quinazoline thione 3 in a nice 75% yield after chromatographic purification.
The structurally related benzoxazin-4-one 4 (Scheme 2) was obtained in one step by the reaction of ferrocenecarbonyl chloride with anthranilic amide in pyridine.Thionation of 4 with P 2 S 5 provided a chromatographically separable mixture containing unreacted 4 (recovered: 17%) and two new compounds: the fully thionated benzothiazine-4-thione (5, 5%) and benzothiazine-4-one (6, 65%), in which only the in-ring oxygen atom was replaced with sulphur.It is noteworthy that the reactivity observed for 4 contrasts with the literature reports 13 suggesting that the reaction of 2-substituted 3,1-benzoxazin-4-ones with P 2 S 5 /NEt 3 proceeds under the replacement of both oxygen atoms to afford exclusively the corresponding benzothiazin-4thiones.
Attempts to prepare 3-amino-2-ferrocenyl-4-quinazolinone by hydrazinolysis 14 of 4 led only to an opened amide-hydrazide 7 as a product of formal hydrolysis.Likewise, attempted cyclisation of 7 in the presence of 2-chloro-1,3-dimethylimidazolidinium chloride failed. 15Instead of the anticipated cyclic product, the reaction afforded a mixture of two rather unexpected condensation products, viz. the cyclic 1,3-dimethylimidazolidin-2-ylidene hydrazide 8 and its opened zwitterionic analogue 9 in 14% and 75% isolated yields, respectively (Scheme 3). 16ll compounds were characterised by 1 H and 13 C{ 1 H} NMR, and IR spectroscopy, conventional and high-resolution electrospray ionisation (ESI) mass spectrometry, and by elemental analysis.Besides, the molecular structures of 1-7 and 9 were determined by single-crystal X-ray diffraction analysis.

Description of the molecular structures
The molecular structure of the starting bis-amide 1, which crystallizes as a defined hemihydrate, 1Á 1 2 H 2 O, 17 is shown in Fig. 1.The molecular geometry of 1 is similar to that reported for simple ferrocene-based amides such as FcCONHPh 18 and fc(CONHPh) 2 19 (Fc = ferrocenyl, fc = ferrocene-1,1 0 -diyl), and for 2-(acetylamino)benzamide. 20The amide plane comprising atoms C11, O1 and N1 in 1 is rotated with respect to its parent cyclopentadienyl ring C(1-5) by 14.7(2)1.Mutual rotation of the benzene ring and its amide pendant (C27, N2, O2) is considerably larger, the respective dihedral angle being 29.3(2)1.These rotations, possibly destabilising the structure due to a decreased conjugation, seem to result from intra-and intermolecular hydrogen bonding interactions.
In fact, the individual molecules of amide 1 fully exploit their H-bonding ability.In the crystal, they assemble into dimers lying around the inversion centres via N-HÁ Á ÁO interactions (A in Fig. 2) and further into infinite columnar stacks via the carboxyl-like double hydrogen bridges (B).An additional intramolecular N-HÁ Á ÁO contact though with a rather acute angle at the H atom (C) is detected between the FcCONH proton and the CONH 2 oxygen.The solvating water molecules (not shown in Fig. 2) reside on the crystallographic two-fold axes and between the columnar stacks, which they interconnect into a three-dimensional array via O1W-H1WÁ Á ÁO1 hydrogen bonds towards the FcCO oxygens (O1WÁ Á ÁO1 = 2.823(2), angle at H1W = 1521).
The overall molecular structure of hydrazide 7 (Fig. 3) compares well with that of the analogous amide 1. Similarly to 1, the 'amide' planes in 7 are rotated with respect to their parent aromatic rings [cf. the dihedral angles 9.0(2)1 for planes (C11, O1, N1) and C(1-5), and 30.1(1)1 for planes (C27, O2, N2) and C(21-26)].The molecules of 7 assemble into 'dimers' via N-HÁ Á ÁO hydrogen bonds (Fig. 4).However, the cross-linking of these dimers is achieved through N-HÁ Á ÁO contacts involving the hydrazide NH 2 (terminal) moieties, which thus take over the role played by the solvent molecules in the structure of 1Á 1 2 H 2 O.As the result, the individual molecules of 7 associate into wavelike layers, which further assemble into a complicated threedimensional network.
The molecular structures of compounds 2-6 are presented in Fig. 5 and 6, respectively.Structural data for these ferrocenylsubstituted heterocycles, which formally differ only by the type of the heteroatoms and their positions within the six-membered ring, are summarised in Table 1.6), Fe-Cg2 1.6463 (7), +Cp1, Cp2 2.15 (8).The ring planes are defined as for the analogous bis-amide 1 (cf.Fig. 1).The crystal structures reveal practically planar arrangements for the entire heterocyclic units (10 atoms) and their attached CQO/CQS bonds.The maximum observed displacement from the mean planes of the bicyclic units of 0.042(1) and 0.045(1) Å are seen for N13 atoms in 2 and 3, respectively.These compounds also show the largest departure of the exo-cyclic O/S atoms from the plane of their parent heterocyclic moiety, the perpendicular distances from the mean ring plane being 0.082(1) Å for O in 2, and 0.071(1) Å from S in 3. The in-ring distances and angles (Table 1) clearly illustrate a distortion of the six-membered heterocyclic ring upon replacement of the oxygen and nitrogen atoms by the relatively larger sulphur.
The heterocyclic units and their bonding cyclopentadienyl ring in 2-6 are rotated from a mutually coplanar arrangement.
The rotation varies both in the magnitude (see c in Table 1) and also in the sense.Whereas the CQO bond in 4 is directed inwards the ferrocene moiety (i.e., towards the Fe atom), the CQO and CQS bonds in all other structurally characterised compounds point away from the ferrocene unit.These rotations not exceeding ca.151 do not seem to destabilise the structures much by, e.g., a decreased conjugation (see DFT computations below), and can be accounted for by the steric factors at molecular level and also the crystal packing effects.
Finally, the ferrocene units in 2-6 are regular, showing only negligible tilting.The observed shortening of the Fe-Cg1 distances as compared to the matched Fe-Cg2 distances, which is relatively small (0.3-0.9%) but systematic and statistically significant, can be explained by a strengthening of the Fe ' Cp1 donation due to an electron density transfer from the ferrocene unit to the electronwithdrawing heterocyclic unit.
Only compounds 2 and 3 possess both NH protons as the typical H-bond donors and suitable H-bond acceptors.Not surprisingly, therefore, the molecules in their crystal structures associate via N-HÁ Á ÁZ (Z = O, S) interactions giving rise to dimers around the crystallographic inversion centres (Fig. 7a).Probably due to its spatial proximity, the adjacent CH proton (H5) becomes involved in a similar interaction (C5-H5Á Á ÁO), too.The molecules further associate via offset pÁ Á Áp stacking interactions of the ferrocene C 5 H 5 ring and the C 6 H 4 ring within the heterocyclic moiety (Fig. 7b).The distances of the ring centroids and the interplanar angles are 3.839(1) Å and 11.08(9)1 for 2, and 3.8559(9) Å and 5.93(8)1 for 3. Since these p-interactions involve molecules related by elemental translation  along the b-axis, they interconnect the H-bonded dimers into infinite columnar stacks.
In contrast, the molecules of 4-6, lacking the NH groups, associate predominantly via pÁ Á Áp interactions.In the case of 4 and 6, these interactions are formed between the C 5 H 5 rings and the heterocyclic moieties in molecules related by elemental translation along the b-axis.A similar interaction dominates in the crystal assembly of 5, involving molecules related by the crystallographic inversion.
The molecular structure of compound 9 is presented in Fig. 8 together with selected geometric data.According to a search in the Cambridge Structural Database, 21 compound 9 represents the only structurally characterised compound possessing an extended (acyclic) (C 3 N 2 )Á Á ÁNÁ Á ÁN-C(O) linkage, where Á Á Á stands for any bond.An additional search in Chemical Abstracts for a similar fragment bearing the 1,3-dimethyl-2-imidazolidinylidene moiety resulted in only a few compounds (o30) 22 that were all formulated conservatively as the tautomeric 2- In our case, the good-quality diffraction data allowed to locate unambiguously the NH protons and thus to formulate compound 9 as a zwitterion (1,3-Me 2 C 3 N 2 )QNH (+) -N (À) -C(O)R Fc (R Fc = 2-(ferrocenylcarboxamido)phenyl).Parameters describing the geometry of the C11(O1)N11 unit in 9 are very similar to those found in 1 and the precursor 7. On the other hand, the other amide moiety, N2 (À) -C27QO2, gains a partial N2 (dÀ) QC27-O2 (dÀ) character, very likely due to an electron density transfer from the negatively charged N2, which in turn results in an elongation of the C27QO2 bond and shortening of the C27-N2 bond.The C28QN3 (+) and N2-N3 bond lengths in 9 are similar to the respective distances in 4-chloro-N-(imidazolidin-2-ylidene)-1H-indazol-1-amine (N-N = 1.402(2)Å, NNQC = 1.307(2)Å), 23 whereas the N2-N3 separation in 9 is significantly longer than the N-N distances reported for 1,2-dibenzoylhydrazine (1.385(3) Å) 24 and benzaldehyde benzoylhydrazone (1.368(7) Å). 25 The extensive electronic delocalisation in the molecule of 9 corresponds with the unique all-planar geometry this compound assumes in the solid state.Taking the amide linker {C11, O1, N1} as the reference plane, the bonding cyclopentadienyl ring is    found rotated at the dihedral angle of 8.2(2)1, while the entire extended pendant comprising as much as 18 atoms [N(1-5), O2 and C(21-32)], which are coplanar within ca.0.07 Å, is rotated by 6.9(2)1.In addition to conjugation, the planar geometry and perhaps also the particular tautomeric form seem to be stabilised by intramolecular N-HÁ Á ÁO contacts that can be detected in the structure albeit with unfavourably acute angles at the hydrogen atoms (see Fig. 8).

Electrochemistry
The electrochemical behaviour of compounds 1-7 was studied by cyclic voltammetry on a stationary platinum disc electrode using 1,2-dichloroethane solutions and Bu 4 N[PF 6 ] as the supporting electrolyte.The representative cyclic voltammograms are shown in Fig. 9 and the pertinent data are summarised in Table 2.
All compounds display one electrochemically reversible redox transition in the anodic region, which is controlled by diffusion as indicated by the peak potentials increasing linearly with the square root of the scan rate (i p p n 1 2 ).Only in the case of thione 3 the primary redox change is complicated by some follow-up processes affording other redox-active species and is associated with a pre-wave (see Fig. S1, ESI †).The observed redox changes, which can be attributed to the ferrocene/ferrocenium couple, occur in a rather narrow range of ca.60 mV for the whole series and at potentials more positive than the ferrocene/ ferrocenium reference (Table 2).The anodic shift corresponds with the overall electron-withdrawing character of the amide and heterocyclic moieties that can be expected to make any electron removal more difficult (cf. the Hammett's s p constants for CONH 2 : 0.36, and 2-pyrimidinyl: 0.53). 26

Theoretical computations
In order to rationalise the observed redox behaviour and geometric structure determined by X-ray diffraction analysis, we studied quinazolinone 2 as the representative theoretically by density functional theory (DFT) calculations.The geometry obtained by DFT computations (B3LYP/6-31G*) for an isolated molecule matched quite well the experimental one.An average relative error of 0.6% was achieved for the bond distances and angles involving the non-hydrogen atoms, while the maximum error of about 2% was observed for the N13-C14 distance (see Table S1, ESI †).The quinazolinone moiety and its bonding cyclopentadienyl ring was found to be almost coplanar with the torsion angle N11-C12-C1-C2 (j) being ca.À51, which is considerably less that the value from the crystal structure data, j = 15.5(2)1.
The discrepancy between j calculated for an isolated molecule and the value determined from X-ray diffraction data was tentatively attributed to crystal packing effects.Indeed, the geometry obtained from DFT calculations (PBE/6-31G*) performed for a periodic structure with four molecules in the unit cell gave j = 151, which is in a perfect agreement with the experimental value.In this case, however, a slightly worse average relative error for the bond length and angles was obtained (ca.1% for the bond lengths and 0.9% for the angles), which is in line with the well known, slightly poorer performance of the PBE functional (that was used to make the calculations of the crystal structure more economical) as compared with B3LYP.
Next, starting from the geometry optimised for an isolated molecule, we carried out a fully relaxed potential energy surface scan (DFT/B3LYP) for this torsion angle and found a second minimum at j = -1721 (Fig. 10).The potential energy difference between the minima is negligible (about 0.02 kJ mol À1 ) with  respect to thermal energy kT at ambient conditions (ca.2.5 kJ mol À1 ).
The energy barriers separating these minima are about 16 and 22 kJ mol À1 high.Similar calculations using PBE functional gave practically identical results.The energy minima were found at j ca.À41 and -1741, and the calculated energy barriers were ca.17 and 24 kJ mol À1 (for a comparison of the two energy profiles, see Fig. S2, ESI †).Considering the height of the energy barriers, one can expect that the ferrocenyl and quinazolinone moieties undergo a fast rotation at room temperature in solution.This is in accordance with the 1 H and 13 C{ 1 H} NMR spectra showing degenerate signals for the CH groups in a and b positions of the substituted cyclopentadienyl ring.It is also noteworthy that structures corresponding to the minima are very nearly mirror images of each other except for a rotation of the unsubstituted cyclopentadienyl ring.Furthermore, we investigated the electronic structure of 2. The highest occupied molecular orbital (HOMO; Fig. 11) was found to be contributed mainly from d-orbitals centred at the iron atom (68%).Since this contribution represents the only major entry (410%) from one particular atom to HOMO, one may expect that the initial oxidation will occur there, which is in accordance with the observed electrochemical behaviour (vide supra).On the other hand, the lowest unoccupied molecular orbital (LUMO; Fig. 11) is more delocalized with major contributions from p-orbitals of the carbon atoms forming the quinazolinone ring (23% for the pivotal atom C18 and 11% for C12; for numbering, see Fig. 5), and further from d-orbitals of the iron atom (15%).
The extensive conjugation in the molecule of 2 is clearly manifested in UV-vis spectra (Fig. 12).For instance, the low-energy absorption (d-d transitions) of 2 appears shifted to lower energies and is more intense (2: l max = 458 nm, e E 220 M À1 cm À1 ) than for unsubstituted ferrocene (l max E 440 nm) 27 and even ferrocenecarboxamide (FcCONH 2 ; l max E 445 nm).
The calculated electrostatic potential (ESP) is shown in Fig. 13 with values coded by colours on a contour of total electron density drawn at the 0.002 a.u.level that roughly corresponds to the Van der Waals envelope. 28The domain with the most negative ESP (most attractive for a positive test charge) is located on the NH group of quinazolinone, whilst the domain with the most positive ESP is localized at the CQO moiety.This corresponds with the solid-state packing based on an assembly of dimers formed via the N-HÁ Á ÁOQC hydrogen bonds.A supportive C-HÁ Á ÁO interaction also detected in the crystal structure (C5-H5Á Á ÁO see Fig. 5) probably reflects a polarisation of this CH group by the negatively charged CQO oxygen from the other molecule, which is indicated by an increased ESP at this H atom as compared to a-CH close to the heterocyclic N atom.the molecular geometry (the molecular parts tend to be close to co-planar) and the electrochemical response (the electron-withdrawing heterocyclic pendant renders the ferrocene oxidation more difficult).

Materials and methods
All syntheses were performed under argon atmosphere with an exclusion of the direct day light.Ferrocenecarbonyl chloride 29 and ferrocenecarboxamide 30 were prepared according to the literature procedures.Solvents used in the syntheses were dried by standing over appropriate drying agents and distilled under argon [dichloromethane (K 2 CO 3 ), pyridine (KOH), dioxane and triethylamine (sodium metal)].Methanol was distilled from sodium methoxide.Anhydrous acetonitrile and ethanol were purchased from Sigma-Aldrich.Other chemicals (Sigma-Aldrich and Alfa-Aesar) and solvents used for crystallizations and in chromatography (Lachner) were used as received.
NMR spectra were recorded with a Varian UNITY Inova 400 MHz spectrometer ( 1 H, 399.95 MHz; 13 C, 100.58 MHz) at 298 K.Chemical shifts (d/ppm) are given relative to internal tetramethylsilane.Infrared spectra were recorded in Nujol mulls with a Nicolet 6700 FTIR spectrometer in the range 400-4000 cm À1 .UV-vis spectra were recorded with Unicam UV300 spectrometer using methanolic solution and 1 cm quartz cells.Electrospray ionization (ESI) mass spectra were obtained with an Esquire 3000 (Bruker; low resolution) or an LTQ Orbitrap XL instrument (Thermo Fisher Scientific; high resolution).
Electrochemical measurements were performed with a computercontrolled potentiostat mAUTOLAB III (Eco Chemie, Netherlands) at room temperature (ca.23 1C) using a standard Metrohm threeelectrode cell equipped by a platinum disc working electrode (2 mm diameter), platinum sheet auxiliary electrode, and a double-junction Ag/AgCl (3 M KCl) reference electrode.The compounds were dissolved in dry 1,2-dichloroethane (Sigma-Aldrich, absolute) to give solutions containing ca. 0.5 mM of the analyte and 0.1 M Bu 4 N[PF 6 ] (Fluka, puriss.for electrochemistry) as the supporting electrolyte.The solutions were deaerated with argon before the measurement and then kept under an argon blanket.The redox potentials (accuracy ca. 5 mV) are given relative to a ferrocene/ ferrocenium reference (E1 0 = 0.46 V under the experiment conditions).

Syntheses
N-[2-(aminocarbonyl)phenyl]ferrocenecarboxamide (1).Anthranilamide (163 mg, 1.2 mmol) and triethylamine (0.33 mL, 2.40 mmol) were added successively to a solution of ferrocenecarbonyl chloride (248 mg, 1.00 mmol) in dioxane (10 mL).The resulting yellow solution was stirred at room temperature for 20 h, and then diluted with ethyl acetate (20 mL) and washed successively with aqueous saturated NaHCO 3 and brine.The organic layer was dried over MgSO 4 and the volatiles were removed under vacuum, leaving an orange residue, which was purified by column chromatography over silica gel using dichloromethane/methanol (20 : 1 v/v) as the eluent.
A single orange band was collected and evaporated to afford analytically pure 1 as a yellow-orange solid (306 mg, 88%).
Analytical data for 8.
The diffraction data (AEh AEk AEl; y max range 27.0-27.51,data completeness Z99.8%) were collected with an Apex II CCD diffractometer (Bruker) equipped with a Cryostream Cooler (Oxford Cryosystems) using graphite monochromated MoKa radiation (l = 0.71073 Å).The data were corrected for absorption using the methods incorporated in the diffractometer software.
The structures were solved by the direct methods (SHELXS97 31 ) and refined by full-matrix least squares based on F 2 (SHELXL97 31 ).All non-hydrogen atoms were refined with anisotropic displacement parameters.The NH and OH hydrogens were identified on the difference density maps and refined as riding atoms with U iso assigned to 1.2 U eq of their bonding atoms.Other hydrogen atoms were included in their calculated positions and refined similarly (riding model).Relevant crystallographic data and structure refinement parameters are available as (Table S2, ESI †).
The geometric data and structural drawings were obtained with a recent version of the PLATON program. 32The numerical values were rounded with respect to their estimated deviations (ESDs) given to one decimal place.Parameters relating to atoms located in constrained positions are given without ESDs.

DFT calculations
The geometry optimization, starting from the experimentally determined solid-state structure of 2, was performed using the density-functional theory (DFT) with Becke's three parameter functional 33 with the non-local Lee-Yang-Parr correlation functional (B3LYP) 34 and the standard 6-31G* basis set with analytically constructed energy gradient as implemented in the Gaussian 09 program package. 35For the stationary points at the potential energy surface (PES), the harmonic vibrational analysis was carried out by using the analytically calculated force-constant matrix to show that the points are a minima.
Similar calculations were done also for the crystal structure using periodic boundary conditions (PBC).As the unit cell contains four molecules, a computationally less intensive method was used, namely a functional developed by Perdew, Burke and Ernzerhof (PBE) 36 with standard 6-31G* basis set.The calculated geometric data (distances and angles of the nonhydrogen atoms) are available as (Table S1, ESI †).

Fig. 5
Fig. 5 View of the molecular structure of 2 showing the displacement ellipsoids at the 30% probability level.

Fig. 6
Fig.6 Views of the molecular structures of compounds 3-6 showing the atom labelling scheme and displacement ellipsoids at the 30% probability level.

Conclusions 2 -
Ferrocenyl-4(3H)-quinazolinone and the related heterocycles differing by the type and position of the heteroatoms (N -O, S) are accessible by the general methods devised for the preparation of their simple organic counterparts though not always in exactly the same manner.As revealed by electrochemical measurements and DFT computations, the directly connected heterocyclic and ferrocene moieties are conjugated.This conjugation affects both