Synthesis, Crystal Structures, and Dft Calculations of Three New Cyano(phenylsulfonyl)indoles and a Key Synthetic Precursor Compound

Three cyano-1-(phenylsulfonyl)indole derivatives, 3-cyano-1-(phenylsulfonyl) indole, (I), 2-cyano-1-(phenylsulfonyl)indole, (II), and 2,3-dicyano-1-(phenylsulfonyl) indole, (III), and a key synthetic precursor 1-(phenylsulfonyl)-1-(1,1-dimethylethyl) indole-3-carboxamide, (IV), have been synthesized and their structures determined by single crystal X-ray crystallography. 3 and Z = 4. (II), C15H10N2O2S, is monoclinic with space group C 2/c and cell constants: 3 and Z = 8. All four compounds have the same indole nitrogen phenylsulfonyl substituent and (I), (II), and (III) are nitrile derivatives. (IV) is a tert-butylamide. In the crystals, the dihedral angle between the mean planes of the indole and phenylsulfonyl groups are 85. Additionally, DFT geometry-optimized molecular orbital calculations were performed and frontier molecular orbitals of each compound are displayed. 377 Correlation between the calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals to the electronic excitation transitions from the absorption spectra of each compound has been proposed.


Introduction
In connection with our interest in developing novel indole chemistry [1], and in view of the enormous recent interest in the synthesis and biological activity of 2-and 3-cyanoindoles [2][3][4][5], we have synthesized three cyano-1-(phenylsulfonyl)indoles (I-III) and the synthetic precursor (IV) (Figure 1) and characterized them with NMR, single-crystal X-ray diffraction, and DFT molecular orbital calculations.These three compounds and the heteroaryl and aryl nitriles are key precursors of aldehydes, amines, amidines, tetrazoles, amides, and other carbonyl compounds [6,7] and are often employed in the synthesis of pharmaceuticals, dyes, agrochemicals, and natural products [8,9].We report here the synthesis, crystal structures, and theoretical calculations for three cyano indole compounds and a precursor, namely

Theoretical Study of (I)
After a DFT geometry optimization calculation, the dihedral angle between the mean planes of the indole and phenylsulfonyl rings becomes 86.2(8)°, an increase of 0.8(6)°.Bond lengths and bond angles show only small changes with the exception of selected torsion angles consistent with the differences in the mean planes changes indicated above (Table 1).These changes suggest that the single weak C-H…O intermolecular interaction involving the indole ring and a sulfonyl oxygen atom plays only a small role in the crystal packing of the molecule (Table 2).
Calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals for (I) show three absorption band envelopes, exhibiting some blue shifts, which are consistent with the experimental data (Figure 6 and Table 3) with λmax values located at 292, 263, and 217 nm, respectively.The bands in the UV region 290-260 nm are assigned to cyano n → π* and π → π* transitions while the other band at 217 nm is assigned to aromatic π → π* transitions.In HOMO the electronic clouds are distributed primarily on the indole ring and cyano group.In HOMO-1 they are located only on the indole ring.In LUMO the electronic clouds are delocalized primarily on the phenyl ring while in LUMO+1 they are located on both the indole and phenyl rings, as well as on the cyano group.In LUMO+2 they are dispersed primarily on the indole ring.Therefore, the first absorption band envelope at 292 nm is assigned to contributions primarily from HOMO-> LUMO.The second absorption band at 263 nm is assigned to overlapping contributions from HOMO-1-> LUMO and HOMO-> LUMO+1.The third absorption band at 217 nm is assigned to overlapping contributions from HOMO-1-> LUMO+1, HOMO-> LUMO+2 and HOMO-1-> LUMO+2, respectively.It is evident that electron transitions among frontier molecular orbitals in (I) are corrsponding to n → π*and π → π* transitions.

Theoretical Study of (II)
After a DFT geometry optimization calculation, the dihedral angle between the mean planes of the indole and phenylsulfonyl rings becomes 84.1(9)°, a decrease of 3.0(8)°.Again, bond lengths and bond angles show only small changes with the exception of selected torsion angles consistent with the differences in the mean planes changes indicated above (Table 1).These changes also suggest that the single weak C-H…O intermolecular interaction involving the indole ring and a sulfonyl oxygen atom plays a small role in the crystal packing of the molecule (Table 2).
Calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals for (II) show three absorption band envelopes, exhibiting some blue shifts, which are consistent with the experimental data (Figure 7 and Table 4) with λmax values located at 310, 279 and 241 nm, respectively.The bands in the UV region 310-280 nm are assigned to cyano n → π* and π → π* transitions while the other band at 241 nm is assigned to aromatic π → π* transitions.In both HOMO and HOMO-1 the electronic clouds are distributed primarily on both the indole ring and cyano group.In LUMO the electronic clouds are delocalized primarily on the indole ring and cyano group while in LUMO+1 and LUMO+2 they are located only the phenyl ring.Electronic transitions are generally paired between the various molecular orbitals of the ground and excited states corresponding to these three band envelopes as indicated in Table 4. Therefore, the first absorption band envelope at 310 nm is assigned to contributions primarily from HOMO-> LUMO.The second absorption band envelope at 279 nm is assigned to overlapping contributions from HOMO-1-> LUMO and HOMO-> LUMO+1.The third absorption band at 241 nm is assigned to overlapping contributions from HOMO-1-> LUMO+1, HOMO-> LUMO+2 and HOMO-1-> LUMO+2, respectively.It is evident that electron transitions among frontier molecular orbitals in (II) are corrsponding to n → π*and π → π* transitions.

Theoretical Study of (III)
After a DFT geometry optimization calculation, the dihedral angle between the mean planes of the indole and phenylsulfonyl rings becomes 82.5(4) °, an increase of 7.3(7)°.Again, bond lengths and bond angles show only small changes with the exception of selected torsion angles consistent with the differences in the mean planes changes indicated above (Table 1).These changes suggest that the two weak intermolecular interactions involving the indole ring (C-H…O) with a sulfonyl oxygen atom and with a cyano group (C-H…N) nitrogen atom play significant roles in the crystal packing of the molecule (Table 2).
Calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals for (III) show two absorption band envelopes, exhibiting some blue shifts, which are consistent with the experimental data (Figure 8 and Table 5) with λmax values located at 298 and 229 nm, respectively.The band in the 300 nm UV region is assigned to cyano n → π* and π → π* transitions while the other band at 229 nm is assigned to aromatic π → π* transitions.In both HOMO and HOMO-1 the electronic clouds are distributed primarily on both the indole ring and cyano groups.In LUMO the electronic clouds are delocalized primarily on the indole ring and cyano group while in LUMO+1 and LUMO+2 they are located primarily on the phenyl ring.Electronic transitions are generally paired between the various molecular orbitals of the ground and excited states corresponding to these two band envelopes as indicated in Table 5.Therefore, the first absorption band envelope at 298 nm is assigned to overlapping contributions primarily from HOMO-> LUMO, HOMO-1-> LUMO and HOMO-> LUMO+1.The second absorption band at 229 nm is assigned to overlapping contributions from HOMO-1-> LUMO+1, HOMO-> LUMO+2 and HOMO-1-> LUMO+2, respectively.Again, it is evident that electron transitions among frontier molecular orbitals in (III) are corrsponding to n → π*and π → π* transitions.

Theoretical Study of (IV)
After a DFT geometry optimization calculation, the dihedral angle between the mean planes of the indole and phenylsulfonyl rings becomes 89.5(3)°, an increase of 0.9(1)°.Again, bond lengths and bond angles show only small changes with the exception of selected torsion angles consistent with the differences in the mean planes changes indicated above (Table 1).These changes suggest that the hydrogen bonds involving the carboxamide ligand (C-H…O and N-H…O) in concert with weak C-H…O intermolecular interactions involving the indole and phenyl groups with the two sulfonyl oxygen atoms play only a small role in the crystal packing of the molecule (Table 2).
Calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals for (IV) show two absorption band envelopes, exhibiting some blue shifts, which are consistent with the experimental data (Figure 9 and Table 6) with λmax values located at 252 and 210 nm, respectively.Both bands in the 250 nm and 230 UV regions areassigned to aromatic π → π* transitions.In HOMO and HOMO-1 the electronic clouds are distributed primarily on the indole ring.In LUMO and LUMO+1 the electronic clouds are delocalized primarily on the phenyl ring while in LUMO+2 they are located only on the indole ring.Electronic transitions are generally paired between the various molecular orbitals of the ground and excited states corresponding to these two band envelopes as indicated in Table 6.Therefore, the first absorption band envelope at 252 nm is assigned to contributions primarily from HOMO-> LUMO and HOMO-1-> LUMO.The second absorption band at 210 nm is assigned to overlapping contributions from HOMO-> LUMO+1, HOMO-> LUMO+2, HOMO-1-> LUMO+1 and HOMO-1-> LUMO+2, respectively.Again, it is evident that electron transitions among frontier molecular orbitals in (IV) are corrsponding to n → π*and π → π* transitions.

Scheme 1. Synthesis of (I).
The mixture was refluxed overnight.The solution was quenched with aqueous saturated NaHCO3 (400 mL) and stirred until evolution of gas ceased.The solution was then extracted with methylene chloride (100 mL).The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a white solid.The solid was purified using flash chromatography (100% CH2Cl2) to give the title compound as a white solid (2.61 g, 88%): mp 416-418 K (lit.mp [18] 424-425 K); 1

Scheme 2. Synthesis of (II).
After stirring for 3 h, a suspension of p-toluenesulfonyl cyanide (840 mg, 4.6 mmol) in dry THF (5.0 mL) was added quickly.The reaction was allowed to slowly reach room temperature overnight.Thereafter, the mixture was quenched by the addition of aqueous saturated NH4Cl (100 mL) and stirred for 1 h.The mixture was extracted with methylene chloride (2 × 50 mL).The organic extracts were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown residue.This was subjected to flash chromatography [hexanes-CH2Cl2 (1:1)] to give the title compound as white needles (330 mg, 38%): mp 386-388 K (Lit.mp [19] 400.5-402K) 1  Crystals suitable for X-ray analysis were grown from ethanol.

Scheme 3. Synthesis of (III).
After stirring for 2 h, a suspension of p-toluenesulfonyl cyanide (434 mg, 2.4 mmol) in dry THF (2.0 mL) was added.The resulting mixture was allowed to slowly reach room temperature overnight.Thereafter, the mixture was quenched by the addition of aqueous saturated NH4Cl (50 mL) and stirred for 1 h.The mixture was extracted with methylene chloride (2 × 30 mL).The organic extracts were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown residue.This was subjected to flash chromatography [hexanes-CH2Cl2 (1:1)] to give the title compound as white needles (280 mg, 59%): mp 431-435 K (lit.mp [20]  UV-vis data collected on a JASCO V-630 from 800-200 nm.Crystals suitable for X-ray analysis were grown from dichloromethane.

X-ray Structure Analysis and Refinement
Individual crystals of compounds (I), (II), (III), and (IV) were mounted on a CryoLoop (Hampton Research, 34 Journey, Aliso Viejo, CA, USA) and placed in a -100 °C compressed air stream on an Agilent Gemini-EOS Single Crystal Autodiffractometer at Keene State College (Agilent Technologies, LTD, Yarnton, England,).Crystallographic data were collected using graphite monochromated 0.71073 Å Mo-K radiation and integrated and corrected for absorption using the CrysAlisRed (Oxford Diffraction, 2010 software package) [21].The structures were solved using direct methods and refined using least-square methods on F-squared [22].The hydrogen atoms were placed in their calculated positions and included in the refinement using the riding model.All other pertinent crystallographic details such as h, k, l ranges, 2 ranges, and R-factors can be found in Table 1.

Computational Details
A density functional theory (DFT) molecular orbital calculation (WebMo Pro [13] with the GAUSSIAN-03 program package [23] employing the B3LYP (Becke three parameter Lee-Yang-Parr exchange correlation functional), which combines the hybrid exchange functional of Becke [24,25] with the gradient correlation functional of Lee, Yang and Parr [23] and the 6-31 G(d) basis set [26] was performed on each of the four compounds.No solvent corrections were made with these calculations.Starting geometries were taken from X-ray refinement data.The optimized results in the free molecule state are, therefore, compared to those in the crystalline state.Experimentally determined oscillator strengths (f) were determined by use of the equation relating them to the molar decadic absorption coefficient (e) (f = 4.32 × 10 −9 •emax•Δ1/2) [27,28].The molar decadic absorption coefficient measures the intensity of the optical absorption at a given wavelength.Deconvolution of the spectra to obtain the emax and Δ1/2 values was carried out by the IGOR program [29].Discrepancies between the experimental and calculated band centers and band intensities exist.However, this does not prohibit us from making informed decisions on the observations since it is generally known that DFT often underestimates HOMO-LUMO gaps, thereby having a tendency to give excitations far too low in energy.All calculations were performed on a workstation PC using default convergence criteria.

Density Functional Theory (DFT) Calculations
A comparison of selected bond angles and bond distances in the crystal to that from the geometry optimized DFT calculations at the B3LYP 6-31G(d) level is given in Table 1.The differences between the two values are within normal ranges and generally consistent with bond lengths and angles for similar types of compounds.In addition, a comparison of the angles between mean planes of the indole and phenylsulfonyl rings in the crystal and with the DFT geometry optimized calculation in concert with strong and weak intermolecular hydrogen bond interactions has been included in a discussion of the structural aspects for each molecule.From a DFT molecular orbital calculation for each compound, surface plots for the two highest occupied molecular orbital (HOMO and HOMO-1) and three lowest unoccupied molecular orbitals (LUMO, LUMO+1, LUMO+2) are displayed to provide visual evidence of the molecular orbitals involved in the spectroscopic electronic energy transitions examined.Based on correlation of the energies of these HOMO-LUMO frontier surfaces to the UV-VIS absorption spectra, electronic excitation transition predications are suggested.

Summary and Conclusions
The crystal and molecular structure of three new cyano(phenylsulfonyl)indoles and a key synthetic precursor have been determined, along with the frontier molecular orbitals of each compound displayed through density function theory (DFT-B3LYP 6-31G(d)) geometry optimization and molecular orbital calculations.Correlation between the calculated molecular orbital energies (eV) for the surfaces of the frontier molecular orbitals to the electronic excitation transitions from the absorption spectrum of each compound has been determined.In each compound, the DFT molecular orbital calculation, supported by a geometry optimization calculation confirmed that the excitation energies of the surfaces of the frontier molecular orbitals from the HOMO-1 and HOMO to LUMO, LUMO+1, LUMO+2, and LUMO+3 electronic excitations closely match the λmax values of the absorption spectra in overlapping contributions from two, three or four of these excitations within each band envelope.In the crystal structures of three compounds, it has been determined that hydrogen bonds and/or weak C-H…O intermolecular interactions play a small role in the crystal packing of each molecule.In compound (III), the presence of a second cyano nitrogen atom plays a significant role in the observed intermolecular interactions and in the crystal packing.This is supported by changes in the mean planes between the rings within the asymmetric unit when a comparison is made between the crystal structures and density functional theory (DFT) geometry optimization calculations.

Figure 2 .Figure 3 .
Figure 2. (a) ORTEP drawing of (I) showing the atom numbering scheme and 50% probability displacement ellipsoids of non-H atoms; (b) The molecular packing for (I) viewed along the b axis.Hydrogen atoms not involved in hydrogen bonding have been removed for clarity.

Figure 4 .
Figure 4. (a) ORTEP drawing of (III) showing the atom numbering scheme and 50% probability displacement ellipsoids of non-H atoms; (b) The molecular packing for (III) viewed along the b axis.Hydrogen atoms not involved in hydrogen bonding have been removed for clarity.

Figure 5 .
Figure 5. (a) ORTEP drawing of (IV) showing the atom numbering scheme and 50% probability displacement ellipsoids of non-H atoms; (b) The molecular packing for (IV) viewed along the a axis.In (IVa) the tertiary butyl group is disordered over two sites in an occupancy ratio 0.544(10):0.456(10).Dashed lines in (IVb) indicate N2-H2N…O3 hydrogen bonding interactions.Hydrogen atoms not involved in hydrogen bonding have been removed for clarity.

Table 3 .
Experimental and calculated energy of molecular orbitals of (I) and associated transitions.

Table 4 .
Experimental and calculated energy of molecular orbitals of (II) and associated transitions.

Table 5 .
Experimental and calculated energy of molecular orbitals of (III) and associated transitions.

Table 6 .
Experimental and calculated energy of molecular orbitals of (IV) and associated transitions.