Synthesis and Conformational Analysis of Sterically Congested ( 4 R )-( − )-1-( 2 , 4 , 6-Trimethylbenzenesulfonyl )-3n-butyryl-4-tert-butyl-2-imidazolidinone : X-Ray Crystallography and Semiempirical Calculations

The crystal structure of (4R)-(−)-1-(2,4,6-trimethylbenzenesulfonyl)-3-n-butyryl-4-tert-butyl-2-imidazolidinone (3) was determined by single-crystal X-ray diffraction. Compound 3 crystallizes in triclinic system in space group P1 ( ̸ = 1). The crystal data are a = 10.6216(5) Å, b = 16.532(1) Å, c = 8.9572(9) Å, ∝= 91.193(6)∘, β = 93.849(6)∘, γ = 88.097(4)∘, V = 1568.2(2) Å3, Z = 3, calc = 1.253 g/cm , μ(CuKα) = 15.98 cm, F 000 = 636.00, T = 20.0C, and R = 0.037. The crystal structure confirmed the occurrence of threemolecules of 3A, 3B, and 3C in which the n-butyrylmoiety adopted the s-transoid conformation. Crystal structure also revealed that the conformation of 2,4,6-trimethylbenzenesulfonyl groups was in anti-position relative to tert-butyl group. The crystal packing showed that three molecules of compound 3 are stacked as a result of intermolecular π-π interactions between the phenyl ring of one molecule and the phenyl ring of the other molecule by approaching each other to an interplanar separation of 5.034 Å. Interestingly, these stacked molecules are also connected by intermolecular CH-π interaction. The conformational analysis of the s-transoid 3A, 3B, and 3C was separately performed by molecular mechanic MM+ force field. Additionally, computational investigation using semiempirical AM1 and PM3methodswas performed to find a correlation between experimental and calculated geometrical parameters. The data obtained suggest that the structural data furnished by the AM1 method is in better agreement with those experimentally determined for the above compound. It has been found that the lowest energetic conformer computed gives approximate correspondence with experimental solid state data.

In such a way and in continuation of our previous report [20] we studied single-crystal X-ray and the theoretical conformational analysis of (4R)-(−)-1-(2,4,6-trimethylbenzenesulfonyl)-3-butyryl-4-tert-butyl-2-imidazolidinone (3), as a cyclic arylsulfonylurea, focusing on the configuration of substituents around the 2-imidazolidinone core and to establish the factors that influence this configuration and if this configuration can be predicted for new substituted 2imidazolidinone.
The data were collected at a temperature of 20 ± 1 ∘ C using the  − 2 scan technique to a maximum 2 value of 120.1 ∘ .Omega scans of several intense reflections, made prior to data collection, had an average width at half-height of 0.28 ∘ with a take-off angle of 6.0 ∘ .Scans of (1.78 + 0.30 tan ) ∘ were made at a speed of 16.0 ∘ /min (in omega).The weak reflections ( < 10.0 ()) were rescanned (maximum of 5 scans) and the counts were accumulated to ensure good counting statistics.Stationary background counts were recorded on each side of the reflection.The ratio of peak counting time to background counting time was 2 : 1.The diameter of the incident beam collimator was 0.5 mm and the crystal to detector distance was 235 mm.The computer-controlled slits were set to 3.0 mm (horizontal) and 3.0 mm (vertical).

Data Reduction.
Of the 4942 reflections which were collected, 4649 were unique ( int = 0.059); equivalent reflections were merged.The intensities of three representative reflections were measured after every 150 reflections.The linear absorption coefficient, , for Cu-K radiation is 16.0 cm −1 and an empirical absorption correction based on azimuthal scans of several reflections was applied which resulted in transmission factors ranging from 0.81 to 1.00.The data were corrected for Lorentz and polarization effects and a correction for secondary extinction were applied (coefficient = 6.35905 −06 ).

Structure Solution and
Refinement.The structure was solved by direct methods [22] and expanded using Fourier techniques [23].The nonhydrogen atoms were refined anisotropically and hydrogen atoms were included but not refined.The final cycle of full-matrix least-squares refinement (Least-squares: function minimized: ∑ (|Fo| − |Fc|) 2 , where  = 1/ 2 (Fo) = [ 2  (Fo) + ( 2 /4)Fo 2 ] −1 and  2  (Fo) = e.s.d.based on counting,  = -factor) was based on 4409 observed reflections ( > 3.00 ()) and 729 variable parameters and converged (largest parameter shift was 0.09 The standard deviation of an observation of unit weight (standard deviation of an observation of unit weight: √ ∑ (|Fo| − |Fc|) 2 /(No − Nv), where: no.= number of observations and nv = number of variables) was 1.26 and the weighting scheme was based on counting statistics and included a factor ( = 0.080) to down-weight the intense reflections.Plots of ∑ (|Fo| − |Fc|) 2 versus |Fo|, reflection order in data collection, sin /, and various classes of indices showed no unusual trends.The maximum and minimum peaks on the final difference Fourier map corresponded to 0.15 and −0.20  − / Å3 , respectively.Neutral atom scattering factors were taken from Cromer and Waber [24] and anomalous dispersion effects were included in Fcalc [25]; the values for Δ  and Δ  were those of Creagh and McAuley [26].The values for the mass attenuation coefficients are those of Creagh and McAuley [26].All calculations were performed using the teXsan [27] crystallographic software package of Molecular Structure Corporation and crystal data summary is given in Table 1.The selected bond lengths, angles, and torsion angles are given in Tables 2-4 and the molecular structure with the atomnumbering scheme and the packing within the cell lattice are shown in Figures 1 and 3, respectively.

Computational Calculations.
All molecular modeling calculations were performed using HyperChem version 8.0.6 [28], running on "Windows Vista" operating system installed on an Intel core 2 duo PC with a 2.66 GHz processor and 2000 Mb RAM.

Conformational Search.
Conformational analyses of isolated molecule 3 (3A, 3B, and 3C) were done in the same way using the procedure which is suggested for conformational flexible compounds when the property of interest is energy [1].Initial X-ray structures for the molecules 3A, 3B and 3C were used for conformational analysis with HyperChem 8.0 [28].The MM+ [29] (calculations in vacuum, bond dipole option for electrostatics, and RMS gradient of 0.01 kcal/mol) conformational searching in torsional space was performed using the multiconformer method [30,31].Each molecule 3A, 3B, and 3C was subjected to a separate conformational search and the most stable conformer was energy minimized using semiempirical MO methods AM1 [32] and PM3 [33] included in MOPAC version 2009 [34] using HyperChem as GUI.Vibration frequencies calculation for each conformer was characterized to be the stable structure (no imaginary frequencies).

Results and Discussion
As a result of the potential conformational flexibility of the substituent groups of compound 3, we have used solid  state molecular structures (as obtained from single crystal X-ray diffraction analysis) to obtain realistic structure as starting geometries for the quantum chemical calculations.Additionally, the data obtained by X-ray diffraction analysis shed light on some interesting features of its molecular structures.Some structural characteristics of compound 3 are the geometrical parameters around the ring nitrogen atoms such as the relative orientation of the n-butyryl and the 2,4,6trimethylbenzenesulfonyl groups at N1 and N2 positions.
Although, the preferred conformation in the solid phase can be different from the solution structure and in gas phase, the X-ray diffraction data are useful for comparative purposes.
Overall, the combination of experimental and computational results can help in understanding the physical and chemical properties of this molecule.
In addition, the structures of molecules 3A, 3B, and 3C were superimposed in order to reveal the conformational differences of the three molecules (Figure 2).The strategy of overlay fit to match 2-imidazolidinone rings and examines any spatial differences between the atoms of the peripheral fragments.The results show that atoms of the n-butyryl, and 2,4,6-trimethylphenylsulfonyl groups occupy different spatial positions relative to the plane of 2-imidazolidinone ring which may explain the existence of such three molecules in one unit cell.To conclude, it is found that the solid state conformations of the three molecules of 3 (3A, 3B, and 3C) in the unit cell are quite similar, showing minor differences in some bond length and bond angle and major differences in some torsion angles at the peripheral substitution.However, and despite the high congestion in the molecular structures of these compounds, they form quiet molecular packing that likely reflects the subtle influence of the diverse intermolecular interactions.
The crystal packing of 3 is indicated in Figure 3.The molecules are arranged in a layer constituted by three molecules of 3A, 3B, and 3C and that are maintained by numbers of CH-O, CH-, and - interactions [45][46][47].The main structural feature of the packing of 3 is that two molecules are quite parallel to each other and connected by - interactions of the two aryl fragments (5.03 Å) with coordinates −4.250, −2.462, and −0.875, while the third molecule was arranged in a lateral arrangement and approximately in opposite direction to the other two molecules.Additionally, the intramolecular interactions within each molecules of 3 involve O atom of sulfonyl fragment and hydrogen atoms from the CH 3 of 2,4,6-trimethylphenyl group (1.902-2.081Å).The main putative interactions CH-O, as inferred by relatively short distances and suitable orientations, are indicated in Figure 3. On the basis of the short distances and the wide angle, the CH-O intermolecular interactions are likely to be quite strong and an important factor to determine the crystal packing; these bonds can be considered as nonclassical hydrogen bonds [45][46][47] involving CH as H-bond donors.Moreover, the third opposite molecule was showing CH- interaction of the alkyl part of the butyryl moiety of this molecule and the aromatic fragment of the middle molecule (3.86 Å).Similarly the CH 3 group of the 2,4,6-trimethylbenzenesulfonyl group of the middle molecule interacted with aromatic moiety of the third opposite lateral molecule through CH- interaction (3.60 Å).Finally, it must be indicated that the relative orientation between two parallel molecules of 3 in the crystal packing and the third opposite lateral molecule might indicate, besides steric suitability, a tendency to minimize the polarity of the crystal (compensating the dipole moments of the molecules) [48].

Computational Studies.
Despite the interesting properties of the 1-arenesulfonyl-2-imidazolidinones, these compounds have been scarcely studied from a computational point of view [20,49,50].Our goal was to compute quantumchemical derived properties that would be useful as starting points for understanding the properties of this type of ring system.Moreover, the other main task of conformational analyses of isolated molecules 3A, 3B, and 3C was to examine the stable conformations and a global energy minimum for each molecule.If there was considerable energy difference between the lowest energy of 3A, 3B, and 3C type of conformer, then we concluded that theoretical calculations predicted one type of geometric molecule.Since, the size and the variety of heteroatoms in the 2-imidazolidinones are considerable, a full semiempirical geometrical optimization is computationally very demanding.This work is simplified, if we use a realistic structure as starting geometry for the MM conformational search and quantum-chemical calculation.Therefore, the structures obtained by X-ray diffraction analysis are suitable to this end.Since compound 3 appears as three independent molecules in the asymmetric unit, the three structures (molecules 3A, 3B, and 3C) were separately submitted to the conformational search using molecular mechanic MM+ and the energy minima conformer together with the highest energy conformer were subjected to full semiempirical AM1 and PM3 geometry optimization (Figures 4 and 5).Each conformer was confirmed as minimum or transition state on the basis of frequency calculation using AM1 results.

Theoretical Calculations.
Taking into account our interest in the structural study of 2-imidazolidinone, the choice of computational methods which could reproduce the experimental data with reasonable agreement was relevant.Thus, we analyzed the conformational behaviour of compound 3 using semiempirical AM1 and PM3 quantumchemical calculations.Conformational performance of the 2imidazolidinone 3 was examined by the rotation and orientation in the space of the flexible tert-butyl, n-butyryl and 2,4,6-trimethylbenzenesulfonyl groups.Heat of formation, relative energies and dipole moment are collected in Table 5 and characteristic torsional angles, bond angles, and bond distance are also tabulated to illustrate the final geometries obtained.For such compound 3 the MM and semiempirical calculations led to six minimum energy conformations (Figures 4 and 5) within energy differences less than 8 kcal/mol (Table 5).Additionally, the molecular structure of compound 3 was determined by MM+ and semiempirical AM1 and PM3 calculations to assess the accuracy of the theoretical methods used for compound 3. Conformations of the single molecules predicted by AM1, more than MM+ and PM3 methods, were approximately similar to that in the crystal (Figure 4).The arrangement around the N2-S1 and N1-C4 bonds mainly determines the geometry of the N-substituent groups.Based on the geometrical comparison, these forms can be classified into two groups characterised by the torsion angle ∠C1-N1-C4-C5 denoted as conformer-A, -B, -C and -D for transoid butyryl fragment and conformer-E and -F for cisoid butyryl fragment (around −23.8 ∘ and 137.9 ∘ , resp.).For each group there are two or more possible orientations of the 2,4,6trimethylbenzenesulfonyl moiety (torsion angle ∠C1-N2-S1-C12) with a similar energy content.However, the relative energy content of these conformers indicates a strong preference for conformations A-B, while the C-F forms are strongly destabilised.Therefore, it seems that the spatial orientations of the O=S=O of 2,4,6-trimethylbenzenesulfonyl and C=O of n-butyryl group relative to C=O of 2-imidazolidinone ring should be affecting the dipole moment as trans-orientation leads to a decrease of this force and vice versa.The high dipole moment represented by cis orientation probably due to the destabilising through-space interactions of the lone pairs of oxygen atoms yields much greater energy differences such as C-F conformations.In light of these findings, A-B conformations were more preferred compared with C-F conformations which are unfavourable and their participation may be negligible.Therefore, it seems that the orientation of n-butyryl group with 2,4,6-trimethylbenzenesulfonyl moiety exerts a significant effect on the conformational preferences of the compound 3 and this behaviour may be attributed to a combination of steric and electronic factors.
The AM1 method shows that the relative orientation of the aryl group of the most stable conformer-A is practically fixed in an anticonformation relative to position of tertbutyl fragment.These features are in concordance with the behaviour of reported molecules [17,18].Moreover, the aryl group can adopt two symmetric and isoenergetic conformations in which the tert-butyl and the aryl groups are syn and anti-positions (torsion angle ∠C1-N2-S1-C12 about −61.7, 61.7 ∘ ).Moreover, the energy content of the three similar conformation of the conformer-A is very close with a slight predominance of the orientation of the 2,4,6trimethylbenzenesulfonyl group as their interconversion requires a low cost (0.05 kcal/mol).

Comparison of the X-Ray and Calculated Structures.
The crystal structure of 3 confirms the approximate behaviour of such compound in the gas phase (theoretical  bond, their interconversion can take place easily.It was suggested that the change in the spatial orientation of the 2,4,6trimethylbenzenesulfonyl group could be facilitated by the intermolecular interaction in the crystal structure.The anticonformation of 2,4,6-trimethylbenzenesulfonyl adopted in the solid state relative to tert-butyl group would be more favourable for their formation due to the CH-O being sterically more accessible with lower dipole moment.These results confirm the flexibility of the 2,4,6-trimethylbenzenesulfonyl group in these 2-imidazolidinone derivatives and the strong dependence on intermolecular interactions as was previously suggested.Moreover, the great similarity between these conformers is the bond length with only 0.05 Å deviation among them.Hence, calculations at the semiempirical levels of the conformational energies of compound 3 indicate that the ideal gas-phase global energy minimum conformation is partially observed in the solid state.Rather, the effects of intermolecular interactions in the crystal structure cause the molecules to adopt higher-energy conformations, which correspond to local minima in the molecular potential energy surface.Finally to probe similarity and differences between the three-dimensional structures of the conformer-A and molecules 3A, 3B, and 3C, molecular superposition has been performed (Figure 6).The strategy of overlay fit to match 2imidazolidinone rings and examines any spatial differences between the atoms of the 4-tert-butyl, n-butyryl, and 2,4,6trimethylbenzenesulfonyl.The results show that atoms of the 4-tert-butyl, butyryl, and arenesulfonyl groups occupy different spatial positions relative to each other as described above.

Conclusion
The crystal structures of (4R)-(−)-1-(2,4,6-trimethylbenzenesulfonyl)-3-n-butyryl-4-tert -butyl-2-imidazolidinone (3) were reported.This compound 3 crystallized in layers formed by crystallographic independent molecules.These crystallographic motifs are the consequence of the interplay of the diverse intermolecular interactions in the crystal packing.The crystal packing showed three molecules of compound 3 were stacked as a result of intermolecular interaction.A computational analysis of compound 3 was performed using the MM+ force field and fully optimized with semiempirical AM1 and PM3 MO methods.The comparison of experimental versus calculated values for the selected bond lengths and angles of 3 is presented and the relative errors in calculated values are less than 3%.Both the experimental and calculated values agree that compound 3 is a sterically congested molecule.Theoretical conformational analyses have pointed out two factors that determine the conformation of the system under investigation.The first one is intermolecular interaction of the crystal packing, such as CH-O, CH-, and - interactions, which stabilises and favours the occurrence of three independent molecules and the second factor is steric hindrance between substituents.The generally reasonable agreement between theoretical and experimental results have confirmed that the method which was applied for the theoretical conformational analysis of 2-imidazolidinone is good and useful for related organic molecules.Therefore, these results must be regarded as approximated and only with qualitative and comparative purposes.Moreover, the small differences between X-ray and calculated structures are consequence of different states of matter.During the theoretical calculation single isolated molecule is considered in vacuum, while many molecules are treated in solid state during X-ray diffraction.However, all the calculated geometric parameters, obtained by three used models (MM+, AM1, and PM3), represent good approximations and they can be applied as groundwork for prediction and exploring the other properties of the conformers.

Supporting Information Available
Crystallographic data for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre as the Supplementary Publication (no.CCDC 734938).
Copies of the data can be obtained, free of charge, through application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.

Figure 2 :
Figure 2: The superposition of the three molecules (molecule 3A: colors blue, molecule 3B: colors yellow, and molecule 3C: colors red) of X-ray structure of compound 3.

Figure 3 :
Figure 3: Crystal packing of compound 3 (a).(b) Shows intermolecular CH-O, CH- (green lines), and - interactions (orange line).Hydrogen atoms are omitted for clarity except hydrogen included in CH-O interaction.

Figure 6 :
Figure 6: The superposition of the theoretical model (conformer-A (colors green))and the three molecules (molecule 3A, colors blue, molecule 3B: colors yellow, and molecule 3C: colors red) of X-ray structure of compound 3.

Table 1 :
Summary of crystal data, intensity data collection, and structure refinement for compound 3 at 20.0 ∘ C.

Table 5 :
Heat of formations, relative energies, dipole moments, and selected geometric parameters for the significant conformations of 3 computed using semiempirical AM1 MO level of theory.Comparative analysis with crystal structure 3 a .
a All values correspond to fully optimized geometries.b Relative energies for the three similar conformations resulted from the separate conformational analysis of 3A, 3B, and 3C around the N1-C4 and N2-S1 bonds: 0.000, 0.110, and 0.05 kcal/mol, respectively.c Values in bold, plain, and italic text corresponding to MM+, AM1, and PM3 geometry optimization, respectively.