Spectroscopic Investigations and DFT Calculations on 3-(Diacetylamino)-2-ethyl- 3H -quinazolin-4-one

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Introduction
Quinazoline derivatives are of interest because they show a variety of biological activities including anti-inflammation [1], antibacterial [2], antispasm [3], anticancer [ , 5], antiobesity [6] and reductase inhibitory properties [7].Quinazolin--one derivatives have been synthesized by various methods, for example, reactions of carbon dioxide with 2aminobenzonitrile without use of a catalyst in water [8]; reactions of N-substituted 2-bromobenzamides with formamide catalysed by CuI and -hydroxy-l-proline [9]; threecomponent reactions of benzyl halides, isatoic anhydride, and primary amines under mild Kornblum conditions [10].We have shown that the quinazoline ring system can be easily modified via lithiation by a lithium reagent such as alkyllithium in anhydrous tetrahydrofuran at low temperature followed by reactions with electrophiles to provide access to substituted derivatives in high yields.Such derivatives might be difficult to synthesize by other means [11][12][13][14][15].
As far as we are aware, there have been no previous reports of quantum chemical calculations or FT-IR and Laser-Raman spectral studies on 3-(diacetylamino)-2-ethyl-3H-quinazolin--one (2).Herein, we report experimental infrared and Raman spectra along with quantum chemical calculations, which correlate well with each other, to enable vibrational frequencies for compound 2 to be assigned.

Experimental Details
2.1.Characterization Techniques.FT-IR spectra over the range 000-00 cm −1 were obtained on solid phase samples at room temperature using a Perkin-Elmer Spectrum Two FT-IR Spectrometer with cm −1 resolution.Raman spectra within the range of 000-100 cm −1 were obtained on solid phase samples using a Renishaw inVia Raman microscope (excitation line at 785 nm from a diode laser; 100 scans, resolution 1 cm −1 ).
Melting point determination was performed on a Gallenkamp melting point apparatus by the open capillary method. 1 H( 5 0 0M H z )a n d 13 C NMR (125 MHz) spectra were recorded on a Bruker AV500 spectrometer in deuterated dimethyl sulfoxide (DMSO- 6 ).Chemical shifts  (ppm) are reported relative to tetramethylsilane (TMS) and coupling constants (J)areinHz.DEPTspectrawereusedtodetectthe 13 C multiplicities.Coupling patterns, integration values, and expected chemical shifts were used to assign signals.The low and high-resolution mass spectra were recorded on Waters GCT Premier and Waters LCT Premier XE instruments, respectively.A Nonius Kappa CCD diffractometer was used to record the X-ray single-crystal diffraction data by the use of graphite-monochromated Mo-K  ,( =0.71073 Å) radiation.The structure was solved by direct methods using SHELXS-9 6[ 1 6 ]a n dr e fi n e dw i t ha l ld a t ao n 2 full-matrix least squares using SHELXL-97 [17].The full crystallographic data (CCDC 971829) for the title compound can be obtained via http://www.ccdc.cam.ac.uk/structures.

Chemicals.
Chemicals and reagents from Sigma-Aldrich were used without further purification and Fischer Scientific silica 60A (35-70 micron) was used in the purification of 2 by column chromatography.

Computational Details
The use of density functional theory (DFT) calculations has increased rapidly for various applications, particularly since accurate nonlocal corrections were introduced.The methods employed in the current work have been used in many previous theoretical studies [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32].Initial atomic coordinates can generally be taken from experimental XRD results or a database.In this work, experimental XRD data and the Gauss View software database have each been used to determine initial atomic coordinates and to optimize the input structure.The most stable structure after optimization was obtained from the initial atomic coordinates taken from the Gauss View database [33].This most stable structure, following optimization, was used for further theoretical analysis.The calculated gas phase groundstatemolecularstructureofthetitlecompoundwas optimized by the use of DFT/B3LYP and DFT/M06-2X methods with the 6-311++G(d,p) basis set, and the calculated optimized structure was used in the vibrational frequency calculations.The calculated harmonic vibrational frequencies were scaled by 0.961 (B3LYP) and 0.9 89 (M06-2X) for use with the 6-311++G(d,p) basis set, respectively [33,3 ].Identical scale factors were used for the entire spectra.The Gauss View molecular visualization program [33] and the Gaussian 03 program [35] were used to calculate vibrational wavenumbers, optimized geometric parameters, and other molecular properties.The calculated vibrational frequencies were assigned via potential energy distribution (PED) analysis of all the fundamental vibration modes by the use of the VEDA program [36,37] that has been used previously [20, 23, 2 , 32, 38, 39].All the vibrational assignments were based on the B3LYP/6-311++G(d,p) level calculations.Consequently, some assignments could correspond to the value of the next or previous vibrational frequency at the M06-2X/6-311++G(d,p) level.
.2. Geometric Structure.The single-crystal X-ray crystallographic analysis of 2 (C 14 H 15 N 3 O 3 ) showed that the crystal belonged to the monoclinic system and the P2 1 /c space group and possessed the following cell dimensions:  = 7.4975 Å,  = 12.0246 Å, and  = 15.1939Åa n d=9 0 ∘ , = 97.399 ∘ , =9 0 ∘ ,a n d = 1358 .39Å3 .Th em e a s u r e d density of compound 2 was 1.336 mg/mm 3 .T able1showsthe bond lengths and bond angles for the optimized theoretical and experimental structures along with the atom numbering scheme (Figure 1).
A sc a nb es e e nf r o mT a b l e1 ,t h eo p t i m i z e dp a r a m e t e r s calculated at both DFT levels differ only slightly from the experimental values, and small variations are to be expected since the calculations correspond to the gas phase rather than the solid state.For example, in the quinazoline moiety, the C -N13 and C -N35 bond lengths are calculated as 1.286 and 1. 01 Å, respectively, by the B3LYP method, and 1.280 and 1.397 Å, respectively, by the M06-2X method, while the experimental values are 1.286 and 1. 00 Å, respectively.Similarly, the N13-C -N35 and C -N35-C1 bond angles were calculated as 121.9 and 123.6 ∘ ,respectively,bytheB3LYP method and 122.3 and 123.9 ∘ ,r e s p e c t i v e l y ,b yt h eM 0 6 -2 X method, while the experimental bond angles were 121.7 and 12 .5∘ ,respectively.
In order to quantify the level of agreement between the experimental and computational results, correlation coefficients ( 2 ) for linear regression analysis of the experimental and theoretical bond angles and lengths were calculated (last row in each section of Table 1).The values are 0.9820/0.9799for bond lengths and 0.9596/0.9599for bond angles for B3LYP/M06-2X.These values show that bond lengths calc u l a t e du s i n gt h eB 3 L Y Pm e t h o da r es l i g h t l yc l o s e rt ot h e experimental data, but bond angles calculated using the M06-2X method are marginally closer to the data obtained experimentally.
.3.Vibrational Analysis.As seen from Figure 1, the molecule h a s3 5a t o m s ,s ot h e r ea r e1 0 5m o t i o n s ,3o fw h i c ha r e translational, 3 of which are rotational, and 99 of which are vibrationmodes.ThemoleculehasC 1 symmetry.The experimental FT-IR and Laser-Raman spectra of compound 2 are compared with the selected theoretical spectra in Figures 2 and 3, respectively (identified bands are those discussed i nt h et e x ta n db o l dn u m b e r si nT a b l e2 ) .Th eo b s e r v e d vibrational frequencies, scaled harmonic vibrational frequencies calculated at both B3LYP and M06-2X levels, and  detailed potential energy distribution (PED) assignments are summarized in Table 2.The harmonic frequencies calculated for the title molecule relate to the gaseous phase, but the experimental ones are obtained for the solid phase.As a result, disagreement between the calculated frequencies and some of the experimental (observed) frequencies is to be expected.A PED analysis was carried out in order to introduce detailed vibrational assignments for compound 2. Within each fundamental wave number, the calculated modes are numbered downwards from the largest to the smallest frequency.
The harmony between the experimental and calculated wavenumbers is shown in Figure ,  experimental frequencies correlate well with the calculated ones, particularly for B3LYP.The relations between the experimental and calculated wavenumbers are linear and given by the following:  Cal = 0.9986 exp − 0.0726 for B3LYP method,  Cal = 0.9927 exp + 5.7907 for M06-2X method. (1) The correlation coefficients ( 2 values) between the experimental and calculated wavenumbers were calculated as  2 = 0.9998 for B3LYP and  2 = 0.9997 for M06-2X.This indicates that the calculation methods gave reasonable agreement with the experimental values, particularly in the case of the B3LYP method.However, this masks significant differences between experimental and calculated values for a few of the vibrational frequencies, which are worthy of individual mention.
. 3.1.Quinazolinone Carbonyl Group Vibrations.The carbonyl group has a strong C=O stretching vibration around 1850-1550 cm −1 [ 5].Differences of 20-30 cm −1 a r eu s e dt oh e l p recognize particular functional groups such as ester, ketone, or amide groups.For compound 2, the quinazolinone ]C = Om o d ei so b s e r v e da sas t r o n gb a n da t1 6 9 3 c m −1 in the IR spectrum and at 169 cm −1 in the Laser-Raman spectrum.Thecalcula tedvaluesare1683cm −1 (B3LYP) and 1721 cm −1 (M06-2X).This demonstrates that although the correlation coefficients  2 are high, individual calculated frequencies can differ significantly from each other and from the experimental values, and in the case of the M06-2X method the calculated carbonyl stretching frequency differs from the experimental value by a sufficiently large margin that it could not be relied on to identify the functional group.In other cases, however, the level of agreement may be greater.For example, ONCC (O1 -N35-C1-C2) is seen at 77 cm −1 in the IR spectrum and calculated at 77 cm −1 by B3LYP and 767 cm −1 by M06-2X.Bending modes OCC (O1 -C1-C2) were not seen in either the IR spectrum or the Raman spectrum, but two such modes were calculated to be at 39 (B3LYP)/ 00 (M06-2X) and 391 (B3LYP)/393 (M06-2X) cm −1 .For similar quinazoline derivatives [ 6,7]  .3.2.C15H16, 17 and C18H19, 20, 21 Group Vibrations.The CH 2 group has 6 vibrational modes (one asymmetrical and one symmetrical stretching, one scissoring, one wagging, one twisting and rocking).The asymmetric stretch ] as CH 2 ,t h e symmetric stretch ] s CH 2 , the scissoring vibrations CH 2 , and the wagging vibration CH 2 appear at 3000 ± 20, 2900 ± 25, 1440 ± 10,and1340 ± 25 cm −1 ,respectively [ 8,9].For compound 2, agreement between the experimental values and those calculated by B3LYP was generally good but there was less good agreement with those calculated by M06-2X (see Table 2).For example, the CH 2 asymmetrical stretching mode was seen at 293 cm −1 in the IR spectrum and 2938 cm −1 in the Raman spectrum.This asymmetrical stretching mode was calculated to be at 2939 (B3LYP)/2922 (M06-2X) cm −1 .TheCH 2 symmetrical stretching mode was observed at 2915 cm −1 in the IR spectrum and 291 cm −1 in the Raman spectrum.The symmetrical stretching mode was calculated to be at 2911 cm −1 by B3LYP, but 2888 cm −1 by M06-2X.Similarly, the CH 2 scissoring and wagging modes were seen at 1 09 and 1328 cm −1 intheIRspectrum,and1 06 and 1333 cm −1 in the Laser-Raman spectrum, respectively.These modes were calculated to be at 1 06 (B3LYP)/1389 (M06-2X) and 1337 (B3LYP)/1331 (M06-2X) cm −1 ,r e s p e ctively.CH 2 twisting and rocking modes appeared at 1260 ± 10 and 800 ± 25 cm −1 , respectively [ 9].For compound 2, the CH 2 twisting and rocking modes were seen at 12 0 and 803 cm −1 in the IR spectrum, 12 7 and 79 cm −1 in the Laser-Raman spectrum, respectively, and calculated to be at 12 6 (B3LYP)/12 6 (M06-2X) and 782 (B3LYP)/78 (M06-2X) cm −1 ,respectively .
The CH 3 group has nine vibrational modes (two asymmetrical and one symmetrical stretching modes, two antisymmetrical deformations, one symmetrical deformation, two rocking modes, and 1 twisting mode).The CH 3 asymmetric stretching vibrations are expected in the 2950-3050 cm −1 region and CH 3 symmetric vibrations in the 2900-2950 cm −1 region [ 8,9].For compound 2 the asymmetric stretching modes were calculated to be at 3003 (B3LYP)/2988 (M06-2X) and 2989 (B3LYP)/2977 (M06-2X) cm −1 , and the symmetric mode at 2928 (B3LYP)/290 (M06-2X) cm −1 .A s y m m e t r i c stretching modes were observed at 3003 cm −1 in the IR spectrum and at 2993 cm −1 in the Laser-Raman spectrum (the two bands appearing within a single envelope in each case), while symmetric stretching modes were observed at 293 cm −1 in the IR and 291 cm −1 in the Laser-Raman spectrum.Again, therefore, the B3LYP method is a better predictor of the experimental values than the M06-2X method.The same trend is observed for some of the other vibrational modes.For example, the symmetrical bending deformation,  s CH 3 , is expected at 1380 ± 25 cm −1 [ 8].The calculated value was 1366 (B3LYP)/1353 (M06-2X) cm −1 , while the observed value was 136 cm −1 in the IR spectrum and 1363 cm −1 in the Laser-Raman spectrum.Similarly, aromatic molecules display a methyl rocking in the neighborhood of 10 5 cm −1 ,a n da second rocking in the region of 970 ± 70 cm −1 ,whichismore difficult to find among the C-H out-of-plane deformations [ 8].For compound 2,theseCH 3 modes were observed at 1038 and 9 cm −1 in the IR spectrum; the first of these bands was observed at 1026 cm −1 in the Laser-Raman spectrum, but the second rocking mode was not observed.These bands were calculated at 1035 (B3LYP)/1038 (M06-2X) and 9 8 (B3LYP)/955 (M06-2X) cm −1 ,respectively.
Although the M06-2X calculated frequencies of some vibrational modes were a little closer to the observed values than the ones calculated by B3LYP, in the overwhelming majority of cases B3LYP provided calculated values that were closertotheobservedvalues(seeTable2).Thisperspectiveis more easily seen in the graphical experimental and calculated spectra shown in Figure 2 (IR) and Figure 3 (Raman).Figure 3 alsorevealsthatthecalculatedintensitiesofsomeofthebands in the Raman spectra were substantially different from the experimentally observed intensities.
Ring C=C stretching vibrations usually occur around 1625-1 30 cm −1 [59].For benzenoid compounds there are two or three bands due to skeletal vibrations; the strongest band is at ca. 1500 cm −1 .The observed and calculated values for compound 2 are shown in Table 2. . .HOMO-LUMO Analysis.Chemical stability is mainly influenced by the frontier orbitals (HOMO and LUMO).The HOMO represents electron-donating capability, while the LUMO represents electron accepting capability [60].The HOMO and LUMO energies of 2 were calculated by the B3LYP/6-311++G(d,p) (Figure 5; positive phase represented i nr e da n dn e g a t i v ep h a s er e p r e s e n t e di ng r e e n )a n dM 0 6 -2X/6-311++G(d,p) methods.A large HOMO-LUMO gap implies a chemically "hard" molecule and a small HOMO-LUMO gap implies a "soft" molecule.The chemical reactivity of a molecule is also related to its "hardness," molecules with lower HOMO-LUMO gaps being more reactive [61].The frontier molecular orbital energy gap therefore helps in understanding the kinetic stability and reactivity of molecules [62,63].
The HOMO-LUMO energy gap calculated for compound 2 is 5.119590 2 e.V by B3LYP/6-311++G(d,p) and 7. 5978802 e.V by M06-2X/6-311++G(d,p).This energy gap reflects the chemical activity of the molecule and influences its biological activity.As is evident from Figure 5, the HOMO is located on the quinazoline rings, the acetylamino group, a n do v e rt h eC 1 = O 1 c a r b o n y lg r o u p .Th eL U M Oi sm o r e focused on the quinazoline ring and the C1=O1 carbonyl group and partially over the C29 atom.
The ionization energy ()a n de l e c t r o na ffi n i t y( )c a n be expressed by HOMO and LUMO orbital energies as = − HOMO and =−  LUMO .The global hardness = 1/2( LUMO − HOMO ).The ionization energy, along with electron affinity, can be used to give electronic chemical potential,  = 1/2( LUMO + HOMO ), the global electrophilicity index = 2 /2, and the softness =1 /  [6 ].Such parameters w er ecalcula t eda n da r eta b ula t edinT a b le3.Th eio niza tio n

Conclusion
In this work, the vibrational modes of newly synthesized 3-(diacetylamino)-2-ethyl-3H-quinazolin--one (2) were studied experimentally by use of FT-IR and Laser-Raman spectra and computationally using DFT/B3LYP and M06-2X methods.The vibrational harmonic frequencies, optimized geometric parameters, molecular orbital energies, and other properties related to HOMO and LUMO energy values of compound 2 were calculated using DFT/B3LYP and M06-2X methods with the 6-311++G(d,p) basis set.The assignments of the vibrational frequencies were made with the help of potential energy distribution (PED) analysis using VEDA software.The theoretical optimized geometric parameters and vibrational frequencies have been found to be in good agreement with the corresponding experimental data and results in the literature.The calculated HOMO and LUMO orbitals and their energies have been used to gain understanding of charge transfer within compound 2.
s e n o t e: C h a n g e s m a d e a s a r e s ul t of p u blis hi n g p r o c e s s e s s u c h a s c o py-e di ti n g, fo r m a t ti n g a n d p a g e n u m b e r s m a y n o t b e r efl e c t e d in t his ve r sio n.Fo r t h e d efi nitiv e ve r sio n of t hi s p u blic a tio n, pl e a s e r ef e r t o t h e p u blis h e d s o u r c e.You a r e a d vis e d t o c o n s ul t t h e p u blis h e r's v e r sio n if yo u wi s h t o cit e t hi s p a p er. Thi s v e r sio n is b ei n g m a d e a v ail a bl e in a c c o r d a n c e wit h p u blis h e r p olici e s.

Figure 1 :
Figure 1: The optimized molecular structure of compound 2.

Figure 2 :
Figure 2: Comparison of observed and calculated infrared spectra of compound 2.

Figure 3 :
Figure 3: Comparison of observed and calculated Raman spectra of compound 2.

Figure :
Figure : Correlation graphics of experimental and theoretical (scaled) wavenumbers of 2.

Table 1 :
Experimental and calculated geometric parameters of compound 2 (figures in bold relate to parameters discussed in the text).

Table 3 :
Comparison of HOMO-LUMO energy gaps and related molecular properties of 2.